Review
BibTex RIS Cite

Year 2025, Volume: 55 Issue: 2, 301 - 317, 23.09.2025
https://doi.org/10.26650/IstanbulJPharm.2025.1603560

Abstract

References

  • Acosta, J. C., O'Loghlen, A., Banito, A., Guijarro, M. V., Augert, A., Raguz, S., Fumagalli, M., Da Costa, M., Brown, C., Popov, N., Takatsu, Y., Melamed, J., d'Adda di Fagagna, F., Bernard, D., Hernando, E., Gil, J. (2008). Chemokine signaling via the CXCR2 receptor reinforces senescence. cell, 133(6), 1006-1018. https://doi.org/10.1016/ j.cell.2008.03.038 google scholar
  • Alessio, N., Aprile, D., Cappabianca, S., Peluso, G., Di Bernardo, G., & Galderisi, U. (2021). Different stages of quiescence, senescence, and cell stress identified by molecular algorithm based on the expression of Ki67, RPS6, and beta- galactosidase activity. International Journal of Molecular Sciences, 22(6), 3102. https://doi.org/10.3390/ijms22063102 google scholar
  • Alexander, K., & Hinds, P. W. (2001). Requirement for p27KIP1 in retinoblastoma pro- tein-mediated senescence. Molecular and Cellular Biology, 21(11), 3616-3631. https://doi.org/10.1128/MCB.21.11.3616-3631.2001 google scholar
  • Alimbetov, D., Davis, T., Brook, A. J., Cox, L. S., Faragher, R. G., Nurgozhin, T., Zhumadilov, Z., Kipling, D. (2016). Suppression of the senescence-associated secretory phenotype (SASP) in human fibroblasts using small molecule inhibitors of p38 MAP kinase and MK2. Biogerontology, 17, 305-315. https://doi.org/10.1007/ s10522-015-9610-z google scholar
  • Alspach, E., Flanagan, K. C., Luo, X., Ruhland, M. K., Huang, H., Pazolli, E., Donlin, M. J., Marsh, T., Piwnica-Worms, D., Monahan, J., Novack, D. V., McAllister, SS., Stewart, S.A. (2014). p38MAPK plays a crucial role in stromal-mediated tumori- genesis. Cancer discovery, 4(6), 716-729. https://doi.org/10.1158/2159-8290.CD- 13-0743 google scholar
  • Althubiti, M., Lezina, L., Carrera, S., Jukes-Jones, R., Giblett, S. M., Antonov, A., Barlev, N., Saldanha, G. S., Pritchard, C. A., Cain, K., Macip, S. (2014). Characterization of novel markers of senescence and their prognostic potential in cancer. Cell death & disease, 5(11), e1528-e1528. https://doi.org/10.1038/cddis.2014.489 google scholar
  • Amor, C., Feucht, J., Leibold, J., Ho, Y-J., Zhu, C., Alonso-Curbelo, D., Mansilla-Soto, J., Boyer, J. A., Li, X., Giavridis, T., Kulick, A., Houlihan, S., Peerschke, E., Friedman, S. L., Ponomarev, V., Piersigilli, A., Sadelain, M., Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. https://doi.org/10.1038/s41586-020-2403-9 google scholar
  • Aschauer, L., & Muller, P. A. (2016). Novel targets and interaction partners of mu- tant p53 Gain-Of-Function. Biochemical Society Transactions, 44(2), 460-466. https://doi.org/10.1042/BST20150261 google scholar
  • Azazmeh, N., Assouline, B., Winter, E., Ruppo, S., Nevo, Y., Maly, A., Meir, K., Witkiewicz, A. K., Cohen, J., Rizou, S. V., Pikarsky, E., Luxenburg, C., Gorgoulis, V. G., Ben-Porath, I. (2020). Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation. Nature communications, 11(1), 2711. https://doi.org/10.1038/s41467-020-16475-3 google scholar
  • Baar, M. P., Brandt, R. M. C., Putavet, D. A., Klein, J. D. D., Derks, K. W. J., Bourgeois, B. R. M., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D. A., van der Pluijm, I., Essers, J., van Cappellen, W. A., van IJcken, W. F., Houtsmuller, A. B., Pothof, J., de Bruin, R. W. F., Madl, T., Hoeijmakers, J. H. J., Campisi, J., & de Keizer, P. L. J. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147. https://doi.org/10. 1016/j.cell.2017.02.031 google scholar
  • Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., Saltness, R., Jeganathan, K. B., Versoza, G. C., Pezeshki, A. M., Khazaie, K., Miller, J. D., & van Deursen, J. M. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189. https://doi.org/10.1038/nature 16932 google scholar
  • Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. https://doi.org/10.1038/nature10600 google scholar
  • Bao, E., Zhou, Y., He, S., Tang, J., He, Y., Zhu, M., Cheng, C., &Wang, Y. (2023). RING box protein-1 (RBX1), a key component of SCF E3 ligase, induced multiple myeloma cell drug-resistance though suppressing p27. Cancer Biology & Therapy, 24(1), 2231670. https://doi.org/10.1080/15384047.2023.2231670 google scholar
  • Beauséjour, C. M., Krtolica, A., Galimi, F., Narita, M., Lowe, S. W., Yaswen, P., & Campisi, J. (2003). Reversal of human cellular senescence: roles of the p53 and p16 pathways. The EMBO journal, 22, 4212 – 4222. https://doi.org/10.1093/emboj/ cdg417 google scholar
  • Blagosklonny, M. V. (2013). Hypoxia, MTOR and autophagy: converging on senescence or quiescence. Autophagy, 9(2), 260-262. https://doi.org/10.4161/auto.22783 google scholar
  • Blain, S. W., Scher, H. I., Cordon-Cardo, C., & Koff, A. (2003). p27 as a target for cancer therapeutics. Cancer Cell, 3(2), 111-115. https://doi.org/10.1016/S1535-6108(03) 00026-6 google scholar
  • Boisvert, F. M., Hendzel, M. J., & Bazett-Jones, D. P. (2000). Promyelocytic leukemia (PML) nuclear bodies are protein structures that do not accumulate RNA. The Journal of cell biology, 148(2), 283-292. https://doi.org/10.1083/jcb.148.2.283 google scholar
  • Bojko, A., Czarnecka-Herok, J., Charzynska, A., Dabrowski, M., & Sikora, E. (2019). Diver- sity of the senescence phenotype of cancer cells treated with chemothera- peutic agents. Cells, 8(12), 1501. https://doi.org/10.3390/cells8121501 google scholar
  • Borrero, L. J. H., & El-Deiry, W. S. (2021). Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1876(1), 188556. https://doi.org/10.1016/j.bbcan.2021.188556 google scholar
  • Brenner, E., Schörg, B. F., Ahmetlić, F., Wieder, T., Hilke, F. J., Simon, N., … Röcken, M. (2020). Cancer immune control needs senescence induction by interferon- dependent cell cycle regulator pathways in tumours. Nature Communications, 11(1), 1335. https://doi.org/10.1038/s41467-020-14987-6 google scholar
  • Bryant, C. S., Kumar, S., Chamala, S., Shah, J., Pal, J., Haider, M., Seward, S., Qazi, A. M., Morris, R., Semaan, A., Shammas, M. A., Steffes, C., Potti, R. B., Prasad, M., Weaver, D. W., & Batchu, R. B. (2010). Sulforaphane induces cell cycle arrest by protecting RB-E2F-1 complex in epithelial ovarian cancer cells. Molecular cancer, 9, 1-9. https://doi.org/10.1186/1476-4598-9-47 google scholar
  • Cao, N., Yu, Y., Zhu, H., Chen, M., Chen, P., Zhuo, M., Mao, Y., Li, L., Zhao, Q., Wu, M., & Ye, M. (2020b). SETDB1 promotes the progression of colorectal cancer via epigenetically silencing p21 expression. Cell Death & Disease, 11(5), 351. https:// doi.org/10.1038/s41419-020-2561-6 google scholar
  • Cao, X., Hou, J., An, Q., Assaraf, Y. G., & Wang, X. (2020a). Towards the overcoming of anticancer drug resistance mediated by p53 mutations. Drug Resistance Updates, 49, 100671. https://doi.org/10.1016/j.drup.2019.100671 google scholar
  • Castilho, R. M., Squarize, C. H., Chodosh, L. A., Williams, B. O., & Gutkind, J. S. (2009). mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell, 5(3), 279-289. https://doi.org/10.1016/j.stem.2009.06.017 google scholar
  • Cayo, A., Segovia, R., Venturini, W., Moore-Carrasco, R., Valenzuela, C., & Brown, N. (2021). mTOR activity and autophagy in senescent cells, a complex partner- ship. International Journal of Molecular Sciences, 22(15), 8149. https://doi.org/ 10.3390/ijms22158149 google scholar
  • Cazzalini, O., Scovassi, A. I., Savio, M., Stivala, L. A., & Prosperi, E. (2010). Multiple roles of the cell cycle inhibitor p21CDKN1A in the DNA damage response. Mutation Research/Reviews in Mutation Research, 704(1-3), 12-20. https://doi.org/10. 1016/j.mrrev.2010.01.009 google scholar
  • Cecchini, M. J., Ishak, C. A., Passos, D. T., Warner, A., Palma, D. A., Howlett, C. J., Driman, D. K., & Dick, F. A. (2015). Loss of the retinoblastoma tumor suppressor correlates with improved outcome in patients with lung adenocarcinoma treated with surgery and chemotherapy. Human Pathology, 46(12), 1922-1934. https://doi. org/10.1016/j.humpath.2015.08.010 google scholar
  • Chandra, T., Kirschner, K., Thuret, J.-Y., Pope, B. D., Ryba, T., Newman, S., Ahmed, K., Samarajiwa, S. A., Salama, R., Carroll, T., Stark, R., Janky, R., Narita, M., Xue, L., Chicas, A., Nũnez, S., Janknecht, R., Hayashi-Takanaka, Y., Wilson, M. D., … Narita, M. (2012). Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation. Molecular Cell, 47(2), 203-214. https://doi.org/10.1016/j.molcel.2012.06.010 google scholar
  • Chen, Y. Q., Cipriano, S. C., Sarkar, F. H., Ware, J. L., & Arenkiel, J. M. (1995). p53- independent induction of p21 (WAF1) pathway is preserved during tumor progression. International Journal of Oncology, 7(4), 889-893. https://doi.org/ 10.3892/ijo.7.4.889 google scholar
  • Cheung, T. H., & Rando, T. A. (2013). Molecular regulation of stem cell quiescence. Nature reviews Molecular Cell Biology, 14(6), 329-340. https://doi.org/10.1038/nrm 3591 google scholar
  • Chipuk, J. E., Kuwana, T., Bouchier-Hayes, L., Droin, N. M., Newmeyer, D. D., Schuler, M., & Green, D. R. (2004). Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science, 303(5660), 1010-1014. https://doi.org/10.1126/science.1092734 google scholar
  • Cho, S., & Hwang, E. S. (2012). Status of mTOR activity may phenotypically differentiate senescence and quiescence. Molecules and Cells, 33, 597-604. http://dx.doi. org/10.1007%2Fs10059-012-0042-1 google scholar
  • Chu, I. M., Hengst, L., & Slingerland, J. M. (2008). The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nature Reviews Cancer, 8(4), 253-267. https://doi.org/10.1038/nrc2347 google scholar
  • Cooks, T., Pateras, I. S., Tarcic, O., Solomon, H., Schetter, A. J., Wilder, S., Lozano, G., Pikarsky, E., Forshew, T., Rozenfeld, N., Harpaz, N., Itzkowitz, S., Harris, C. C., Rotter, V., Gorgoulis, V. G., & Oren, M. (2013). Mutant p53 prolongs NF-κB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell, 23(5), 634-646. https://doi.org/10.1016/j.ccr.2013. 03.022 google scholar
  • Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y. U., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P.-Y., & Campisi, J. (2008). Senescence-associated secretory pheno- types reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biology, 6(12), e301. https://doi.org/10.1371/journal. pbio.0060301 google scholar
  • Correia-Melo, C., Marques, F. D. M., Anderson, R., Hewitt, G., Hewitt, R., Cole, J., Carroll, B. M., Miwa, S., Birch, J., Merz, A., Rushton, M. D., Charles, M., Jurk, D., Tait, S. W. G., Czapiewski, R., Greaves, L., Nelson, G., Bohlooly-Y, M., Rodriguez-Cuenca, S.,… Passos, J. F. (2016). Mitochondria are required for pro‐ageing features of the senescent phenotype. The EMBO Journal, 35(7), 724-742. https://doi.org/10. 15252/embj.201592862 google scholar
  • D'adda Di Fagagna, F. (2008). Living on a break: cellular senescence as a DNA-damage response. Nature Reviews Cancer, 8(7), 512-522. https://doi.org/10.1038/nrc 2440 google scholar
  • De Blander, H., Morel, A. P., Senaratne, A. P., Ouzounova, M., & Puisieux, A. (2021). Cel- lular plasticity: a route to senescence exit and tumorigenesis. Cancers, 13(18), 4561. https://doi.org/10.3390/cancers13184561 google scholar
  • De Chiara, G., Marcocci, M. E., Torcia, M., Lucibello, M., Rosini, P., Bonini, P., Higashimoto, Y., Damonte, G., Armirotti, A., Amodei, S., Palamara, A. T., Russo, T., Garaci, E., & Cozzolino, F. (2006). Bcl-2 Phosphorylation by p38 MAPK: identification of target sites and biologic consequences. Journal of Biological Chemistry, 281(30), 21353-21361. https://doi.org/10.1074/jbc.M511052200″, google scholar
  • de Keizer, P. L. J., Packer, L. M., Szypowska, A. A., Riedl-Polderman, P. E., van den Broek, N. J. F., de Bruin, A., Dansen, T. B., Marais, R., Brenkman, A. B., & Burgering, B. M. T. (2010). Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence. Cancer Research, 70(21), 8526-8536. https://doi.org/10.1158/0008-5472.CAN-10-1563 google scholar
  • Delfarah, A., Hartel, N. G., Zheng, D., Yang, J., & Graham, N. A. (2021). Identification of a proteomic signature of senescence in primary human mammary epithelial cells. Journal of Proteome Research, 20(11), 5169-5179. https://doi.org/10.1021/ acs.jproteome.1c00659 google scholar
  • Delmas, V., Beermann, F., Martinozzi, S., Carreira, S., Ackermann, J., Kumasaka, M., Denat, L., Goodall, J., Luciani, F., Viros, A., Demirkan, N., Bastian, B. C., Goding, C. R., & Larue, L. (2007). β-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development. Genes & Development, 21(22), 2923-2935. https://doi.org/10.1101/ gad.450107 google scholar
  • Demidenko, Z. N., & Blagosklonny, M. V. (2008). Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle, 7(21), 3355-3361. https:// doi.org/10.4161/cc.7.21.6919 google scholar
  • Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., Schurra, C., Garre’, M., Nuciforo, P. G., Bensimon, A., Maestro, R., Pelicci, P. G., & d’Adda di Fagagna, F. (2006). Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature, 444(7119), 638-642. https://doi.org/ 10.1038/nature05327 google scholar
  • Dolan, D. W., Zupanic, A., Nelson, G., Hall, P., Miwa, S., Kirkwood, T. B., & Shanley, D. P. (2015). Integrated stochastic model of DNA damage repair by non-homologous end joining and p53/p21-mediated early senescence signalling. PLoS Computational Biology, 11(5), e1004246. https://doi.org/10.1371/journal.pcbi.1004246 google scholar
  • Donnini, S., Monti, M., Castagnini, C., Solito, R., Botta, M., Schenone, S., Giachetti, A., & Ziche, M. (2007). Pyrazolo–pyrimidine‐derived c‐Src inhibitor reduces angio- genesis and survival of squamous carcinoma cells by suppressing vascular endothelial growth factor production and signaling. International Journal of Cancer, 120(5), 995-1004. https://doi.org/10.1002/ijc.22410 google scholar
  • Duy, C., Li, M., Teater, M., Meydan, C., Garrett-Bakelman, F. E., Lee, T. C., Chin, C. R., Durmaz, C., Kawabata, K. C., Dhimolea, E., Mitsiades, C. S., Doehner, H., google scholar
  • D'Andrea, R. J., Becker, M. W., Paietta, E. M., Mason, C. E., Carroll, M., & Melnic, A. M. (2021). Chemotherapy induces senescence-like resilient cells capable of initiating AML recurrence. Cancer Discovery, 11(6), 1542-1561. https://doi.org/10. 1158/2159-8290.CD-20-1375 google scholar
  • Eggert, T., Wolter, K., Ji, J., Ma, C., Yevsa, T., Klotz, S., Medina-Echeverz, J., Longerich, T., Forgues, M., Reisinger, F., Heikenwalder, M., Wang, X. W., Zender, L., & Greten, T. F. (2016). Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell, 30(4), 533-547. https://doi.org/10.1016/j.ccell.2016.09.003 google scholar
  • El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B (1993). WAF1, a potential mediator of p53 tumor suppression. Cell, 75(4), 817-825. https://doi.org/10.1016/0092-8674 (93)90500-p google scholar
  • Evangelou, K., Belogiannis, K., Papaspyropoulos, A., Petty, R., & Gorgoulis, V. G. (2023). Escape from senescence: molecular basis and therapeutic ramifications. The Journal of Pathology, 260(5), 649-665. https://doi.org/10.1002/path.6164 google scholar
  • Faget, D. V., Ren, Q., & Stewart, S. A. (2019). Unmasking senescence: context-dependent effects of SASP in cancer. Nature Reviews Cancer, 19(8), 439-453. https://doi. org/10.1038/s41568-019-0156-2 google scholar
  • Fan, D. N. Y., & Schmitt, C. A. (2019). Genotoxic stress-induced senescence. In M. Demaria (Ed.), Cellular senescence (Methods in Molecular Biology, Vol. 1896, pp. 455–469). Humana Press. https://doi.org/10.1007/978-1-4939-8931-7_10 google scholar
  • Frazier, M. W., He, X., Wang, J., Gu, Z., Cleveland, J. L., & Zambetti, G. P. (1998). Activation of c-myc gene expression by tumor-derived p53 mutants requires a discrete C-terminal domain. Molecular and Cellular Biology, 18(7), 3735–3743. https:// doi.org/10.1128/MCB.18.7.3735 google scholar
  • Freund, A., Patil, C. K., & Campisi, J. (2011). p38MAPK is a novel DNA damage response‐independent regulator of the senescence‐associated secretory phe- notype. The EMBO Journal, 30(8), 1536-1548. https://doi.org/10.1038/emboj. 2011.69 google scholar
  • Furukawa, K., & Kondo, T. (1998). Identification of the lamina‐associated‐polypeptide‐ 2‐binding domain of B‐type lamin. European Journal of Biochemistry, 251(3), 729-733. https://doi.org/10.1046/j.1432-1327.1998.2510729.x google scholar
  • Gao, H., Zhou, F., Li, R., Yuan, J., & Ye, L. (2023). E2F1 inhibits cellular senescence and promotes oxaliplatin resistance in colorectal cancer. Annals of Translational Medicine, 11(4), 185. https://doi.org/10.21037/atm-22-4054 google scholar
  • Gao, X. L., Zhang, M., Tang, Y. L., & Liang, X. H. (2017). Cancer cell dormancy: mecha- nisms and implications of cancer recurrence and metastasis. OncoTargets and Therapy, 2017(10), 5219-5228.. https://doi.org/10.2147/ott.s140854 google scholar
  • García-Fernández, R. A., García-Palencia, P., Sánchez, M. Á., Gil-Gómez, G., Sánchez, B., Rollán, E., Martín-Caballero, J., & Flores, J. M. (2011). Combined loss of p21waf1/cip1 and p27kip1 enhances tumorigenesis in mice. Laboratory investigation, 91(11), 1634-1642. https://doi.org/10.1038/labinvest.2011.133 google scholar
  • Gartel, A. L., & Radhakrishnan, S. K. (2005). Lost in transcription: p21 repression, mechanisms, and consequences. Cancer Research, 65(10), 3980-3985. https:// doi.org/10.1158/0008-5472.CAN-04-3995 google scholar
  • Ghanem, A., Al-Karmalawy, A. A., Abd El Maksoud, A. I., Hanafy, S. M., Emara, H. A., Saleh, R. M., & Elshal, M. F. (2022). Rumex Vesicarius L. extract improves the efficacy of doxorubicin in triple-negative breast cancer through inhibiting Bcl2, mTOR, JNK1 and augmenting p21 expression. Informatics in Medicine Unlocked, 29, 100869. https://doi.org/10.1016/j.imu.2022.100869 google scholar
  • Ghosh, D., Nandi, S., & Bhattacharjee, S. (2018). Combination therapy to checkmate Glioblastoma: clinical challenges and advances. Clinical and Translational Medicine, 7(1), 33. https://doi.org/10.1186/s40169-018-0211-8 google scholar
  • Giacinti, C., & Giordano, A. (2006). RB and cell cycle progression. Oncogene, 25(38), 5220-5227. https://doi.org/10.1038/sj.onc.1209615 google scholar
  • Glück, S., Guey, B., Gulen, M. F., Wolter, K., Kang, T.-W., Schmacke, N. A., Bridgeman, A., Rehwinkel, J., Zender, L., & Ablasser, A. (2017). Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nature Cell Biology, 19(9), 1061-1070. https://doi.org/10.1038/ncb3586 google scholar
  • Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., Gil, J., Hara, E., Krizhanovsky, V., Jurk, D., Maier, A. B., Narita, M., Niedernhofer, L., Passos, J. F., Robbins, P. D.,… Demaria, M. (2019). Cellular senescence: defining a path forward. Cell, 179(4), 813-827. https://doi.org/10.1016/j.cell.2019.10.005 google scholar
  • Gu, C., Peng, H., Lu, Y., Yang, H., Tian, Z., Yin, G., Zhang, W., Lu, S., Zhang, Y., & Yang, Y. (2017). BTK suppresses myeloma cellular senescence through activat- ing AKT/P27/Rb signaling. Oncotarget, 8(34), 56858. https://doi.org/10.18632/ oncotarget.18096 google scholar
  • Gu, Y., Xu, T., Fang, Y., Shao, J., Hu, T., Wu, X., Shen, H., Xu, Y., Zhang, J., Song, Y., Xia, Y., Shu, Y., & Ma, P. (2024). CBX4 counteracts cellular senescence to desensitize gastric cancer cells to chemotherapy by inducing YAP1 SUMOylation. Drug Resistance Updates, 77, 101136. https://doi.org/10.1016/j.drup.2024.101136 google scholar
  • Guan, D., & Kao, H. Y. (2015). The function, regulation and therapeutic implications of the tumor suppressor protein, PML. Cell & Bioscience, 5, 1-14. https://doi.org/ 10.1186/s13578-015-0051-9 google scholar
  • Gubern, A., Joaquin, M., Marquès, M., Maseres, P., Garcia-Garcia, J., Amat, R., González- Nuñez, D., Oliva, B., Real, F. X., de Nadal, E., & Posas, F. (2016). The N-terminal phosphorylation of RB by p38 bypasses its inactivation by CDKs and prevents proliferation in cancer cells. Molecular Cell, 64(1), 25-36. https://doi.org/10. 1016/j.molcel.2016.08.015 google scholar
  • Guo, Q., Lan, F., Yan, X., Xiao, Z., Wu, Y., & Zhang, Q. (2018). Hypoxia exposure induced cisplatin resistance partially via activating p53 and hypoxia inducible factor‑1α in non‑small cell lung cancer A549 cells. Oncology Letters, 16(1), 801-808. https://doi.org/10.3892/ol.2018.8767 google scholar
  • Han, J., Wu, J., & Silke, J. (2020). An overview of mammalian p38 mitogen- activated protein kinases, central regulators of cell stress and receptor signal- ing. F1000Research, 9, 653. https://doi.org/10.12688/f1000research.22092.1 google scholar
  • Haq, R., Brenton, J. D., Takahashi, M., Finan, D., Rottapel, R., & Zanke, B. (2002). Constitu- tive p38HOG mitogen-activated protein kinase activation induces permanent cell cycle arrest and senescence. Cancer Research, 62(17), 5076-5082. Retrieved from https://pubmed.ncbi.nlm.nih.gov/12208764/ google scholar
  • Hernandez-Segura, A., Nehme, J., & Demaria, M. (2018). Hallmarks of cellular senes- cence. Trends in Cell Biology, 28(6), 436-453. https://doi.org/10.1016/j.tcb.2018. 02.001 google scholar
  • Herranz, N., & Gil, J. (2018). Mechanisms and functions of cellular senescence. The Journal of Clinical Investigation, 128(4), 1238-1246. https://doi.org/10.1172/JCI 95148 google scholar
  • Herranz, N., Gallage, S., Mellone, M., Wuestefeld, T., Klotz, S., Hanley, C. J., Raguz, S., Acosta, J. C., Innes, A. J., Banito, A., Georgilis, A., Montoya, A., Wolter, K., Dharma- lingam, G., Faull, P., Carroll, T., Martínez-Barbera, J. P., Cutillas, P., Reisinger, F., … Gil, J. (2015). mTOR regulates MAPKAPK2 translation to control the senescence- associated secretory phenotype. Nature Cell Biology, 17(9), 1205-1217. https:// doi.org/10.1038/ncb3225 google scholar
  • Hilgendorf, K. I., Leshchiner, E. S., Nedelcu, S., Maynard, M. A., Calo, E., Ianari, A., Walen- sky, L. D., & Lees, J. A. (2013). The retinoblastoma protein induces apoptosis directly at the mitochondria. Genes & Development, 27(9), 1003-1015. https:// doi.org/10.1101/gad.211326.112 google scholar
  • Hoare, M., Ito, Y., Kang, T.-W., Weekes, M. P., Matheson, N. J., Patten, D. A., Shetty, S., Parry, A. J., Menon, S., Salama, R., Antrobus, R., Tomimatsu, K., Howat, W., Lehner, P. J., Zender, L., & Narita, M. (2016). NOTCH1 mediates a switch between two distinct secretomes during senescence. Nature Cell Biology, 18(9), 979-992. https://doi. org/10.1038/ncb3397 google scholar
  • Hoque, M. M., Iida, Y., Kotani, H., & Harada, M. (2024). Senolysis of gemcitabine‐ induced senescent human pancreatic cancer cells. Cancer Reports, 7(4), e2075. https://doi.org/10.1002/cnr2.2075 google scholar
  • Hsu, C. H., Altschuler, S. J., & Wu, L. F. (2019). Patterns of early p21 dynamics determine proliferation-senescence cell fate after chemotherapy. Cell, 178(2), 361-373. https://doi.org/10.1016/j.cell.2019.05.041 google scholar
  • Huggins, C. J., Malik, R., Lee, S., Salotti, J., Thomas, S., Martin, N., Quiñones, O. A., Alvord, W. G., Olanich, M. E., Keller, J. R., & Johnson, P. F. (2013). C/EBPγ suppresses senescence and inflammatory gene expression by heterodimerizing with C/ EBPβ. Molecular and Cellular Biology. https://doi.org/10.1128/MCB.01674-12 google scholar
  • Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W., & Raulet, D. H. (2013). p53- dependent chemokine production by senescent tumor cells supports NKG2D- dependent tumor elimination by natural killer cells. Journal of Experimental Medicine, 210(10), 2057-2069. https://doi.org/10.1084/jem.20130783 google scholar
  • Imai, Y., Takahashi, A., Hanyu, A., Hori, S., Sato, S., Naka, K., Hirao, A., Ohtani, N., & Hara, E. (2014). Crosstalk between the Rb pathway and AKT signaling forms a quiescence-senescence switch. Cell Reports, 7(1), 194-207. https://doi.org/10. 1016/j.celrep.2014.03.006 google scholar
  • Iwasa, H., Han, J., & Ishikawa, F. (2003). Mitogen‐activated protein kinase p38 defines the common senescence‐signalling pathway. Genes to Cells, 8(2), 131-144. https://doi.org/10.1046/j.1365-2443.2003.00620.x google scholar
  • Jin, S., Tong, T., Fan, W., Fan, F., Antinore, M. J., Zhu, X., Mazzacurati, L., Li, X., Petrik, K. L., Rajasekaran, B., Wu, M., & Zhan, Q. (2002). GADD45-induced cell cycle G2- M arrest associates with altered subcellular distribution of cyclin B1 and is independent of p38 kinase activity. Oncogene, 21(57), 8696-8704. https://doi. org/10.1038/sj.onc.1206034 google scholar
  • Jin, X., Ding, D., Yan, Y., Li, H., Wang, B., Ma, L., Ye, Z., Ma, T., Wu, Q., Rodrigues, D. N., Kohli, M., Jimenez, R., Wang, L., Goodrich, D. W., de Bono, J., Dong, H., Wu, H., Zhu, R., & Huang, H. (2019). Phosphorylated RB promotes cancer immunity by inhibiting NF-κB activation and PD-L1 expression. Molecular Cell, 73(1), 22-35. https://doi.org/10.1016/j.molcel.2018.10.034 google scholar
  • Joaquin, M., de Nadal, E., & Posas, F. (2017). An RB insensitive to CDK regulation. Molecular & Cellular Oncology, 4(1), e1268242. https://doi.org/10.1080/23723556. 2016.1268242 google scholar
  • Johmura, Y., Yamanaka, T., Omori, S., Wang, T., Sugiura, Y., Matsumoto, M., Suzuki, N., Kumamoto, S., Yamaguchi, K., Hatakeyama, S., Takami, T., Yamaguchi, R., Shimizu, E., Ikeda, K., Okahashi, N., Mikawa, R., Suematsu, M., Arita, M., Sugimoto, M., … Nakanishi, M. (2021). Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science, 371(6526), 265-270. https://doi.org/ 10.1126/science.abb5916 google scholar
  • Jung, S. H., Hwang, H. J., Kang, D., Park, H. A., Lee, H. C., Jeong, D., Lee, K., Park, H. J., Ko, Y.-G., & Lee, J.-S. (2019). mTOR kinase leads to PTEN-loss-induced cellular senescence by phosphorylating p53. Oncogene, 38(10), 1639-1650. https://doi. org/10.1038/s41388-018-0521-8 google scholar
  • Katoh, M., & Katoh, M. (2022). WNT signaling and cancer stemness. Essays in Biochemistry, 66(4), 319-331. https://doi.org/10.1042/EBC20220016 google scholar
  • Kim, E., Giese, A., & Deppert, W. (2009). Wild-type p53 in cancer cells: when a guardian turns into a blackguard. Biochemical Pharmacology, 77(1), 11-20. https://doi. org/10.1016/j.bcp.2008.08.030 google scholar
  • Kim, K. M., Noh, J. H., Bodogai, M., Martindale, J. L., Yang, X., Indig, F. E., Basu, S. K., Ohnuma, K., Morimoto, C., Johnson, P. F., Biragyn, A., Abdelmohsen, K., & Gorospe, M. (2017). Identification of senescent cell surface targetable protein DPP4. Genes & Development, 31(15), 1529-1534. https://doi.org/10.1101/gad. 302570.117 google scholar
  • Kitaura, H., Shinshi, M., Uchikoshi, Y., Ono, T., Tsurimoto, T., Yoshikawa, H., Iguchi- Ariga, S. M. M., & Ariga, H.. (2000). Reciprocal regulation via protein-protein interaction between c-Myc and p21 cip1/waf1/sdi1 in DNA replication and transcription. Journal of Biological Chemistry, 275(14), 10477-10483. https://doi. org/10.1074/jbc.275.14.10477 google scholar
  • Kohli, J., Wang, B., Brandenburg, S. M., Basisty, N., Evangelou, K., Varela-Eirin, M., Campisi, J., Schilling, B., Gorgoulis, V., & Demaria, M. (2021). Algorithmic assess- ment of cellular senescence in experimental and clinical specimens. Nature Protocols, 16(5), 2471-2498. https://doi.org/10.1038/s41596-021-00505-5 google scholar
  • Kopp, H. G., Hooper, A. T., Shmelkov, S. V., & Rafii, S. (2007). ß-Galactosidase staining on bone marrow. The osteoclast pitfall. Histology and Histopathology. https:// doi.org/10.14670/hh-22.971 google scholar
  • Kreis, N. N., Louwen, F., & Yuan, J. (2019). The multifaceted p21 (Cip1/Waf1/CDKN1A) in cell differentiation, migration and cancer therapy. Cancers, 11(9), 1220. https:// doi.org/10.3390/cancers11091220 google scholar
  • Kuilman, T., Michaloglou, C., Vredeveld, L. C. W., Douma, S., van Doorn, R., Desmet, C. J., Aarden, L. A., Mooi, W. J., & Peeper, D. S. (2008). Oncogene-induced senes- cence relayed by an interleukin-dependent inflammatory network. Cell, 133(6), 1019-1031. https://doi.org/10.1016/j.cell.2008.03.039 google scholar
  • Kumar, B., Koul, S., Petersen, J., Khandrika, L., Hwa, J. S., Meacham, R. B., Wilson, S., & Koul, H. K. (2010). p38 mitogen-activated protein kinase–driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity. Cancer Research, 70(2), 832-841. https://doi.org/10.1158/0008-5472. CAN-09-2918 google scholar
  • Kwak, A.-W., Park, J. W., Lee, S.-O., Lee, J.-Y., Seo, J.-H., Yoon, G., Lee, M.-H., Choi, J.-S., & Shim, J.-H. (2022). Isolinderalactone sensitizes oxaliplatin-resistance colorec- tal cancer cells through JNK/p38 MAPK signaling pathways. Phytomedicine, 105, 154383. https://doi.org/10.1016/j.phymed.2022.154383 google scholar
  • Kwong, J., Hong, L., Liao, R., Deng, Q., Han, J., & Sun, P. (2009). p38α and p38γ mediate oncogenic ras-induced senescence through differential mechanisms. Journal of Biological Chemistry, 284(17), 11237-11246. https://doi.org/10.1074/jbc.M 808327200 google scholar
  • Laberge, R.-M., Sun, Y., Orjalo, A. V., Patil, C. K., Freund, A., Zhou, L., Curran, S. C., Davalos, A. R., Wilson-Edell, K. A., Liu, S., Limbad, C., Demaria, M., Li, P., Hubbard, G. B., Ikeno, Y., Javors, M., Desprez, P.-Y., Benz, C. C., Kapahi, P., Nelson, P. S., & Campisi, J. (2015). MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nature Cell Biology, 17(8), 1049-1061. https://doi.org/10.1038/ncb3195 google scholar
  • Lafarga, V., Cuadrado, A., Lopez de Silanes, I., Bengoechea, R., Fernandez-Capetillo, O., & Nebreda, A. R. (2009). p38 Mitogen-activated protein kinase-and HuR- dependent stabilization of p21Cip1 mRNA mediates the G1/S checkpoint. Molecular and Cellular Biology, 29(16), 4341-4351. https://doi.org/10.1128/MCB. 00210-09 google scholar
  • Le, O. N. L., Rodier, F., Fontaine, F., Coppe, J.-P., Campisi, J., DeGregori, J., Laverdière, C., Kokta, V., Haddad, E., & Beauséjour, C. M. (2010). Ionizing radiation‐induced long‐term expression of senescence markers in mice is independent of p53 and immune status. Aging Cell, 9(3), 398-409. https://doi.org/10.1111/j.1474- 9726.2010.00567.x google scholar
  • Lee, B. Y., Han, J. A., Im, J. S., Morrone, A., Johung, K., Goodwin, E. C., Kleijer, W. J., DiMaio, D., & Hwang, E. S. (2006). Senescence‐associated β‐galactosidase is lysosomal β‐galactosidase. Aging cell, 5(2), 187-195. https://doi.org/10.1111/j. 1474-9726.2006.00199.x google scholar
  • Lee, H. L., Lin, C. S., Kao, S. H., & Chou, M. C. (2017). Gallic acid induces G1 phase arrest and apoptosis of triple-negative breast cancer cell MDA-MB-231 via p38 mitogen-activated protein kinase/p21/p27 axis. Anti-cancer drugs, 28(10), 1150-1156. https://doi.org/10.1097/cad.0000000000000565 google scholar
  • Lee, S., & Schmitt, C. A. (2019). The dynamic nature of senescence in cancer. Nature cell biology, 21(1), 94-101. https://doi.org/10.1038/s41556-018-0249-2 google scholar
  • Leelahavanichkul, K., Amornphimoltham, P., Molinolo, A. A., Basile, J. R., Koon- tongkaew, S., & Gutkind, J. S. (2014). A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogene- sis. Molecular Oncology, 8(1), 105-118. https://doi.org/10.1016/j.molonc.2013.10. 003 google scholar
  • Leontieva, O. V., & Blagosklonny, M. V. (2013). CDK4/6-inhibiting drug substitutes for p21 and p16 in senescence: duration of cell cycle arrest and MTOR activity determine geroconversion. Cell Cycle, 12(18), 3063-3069. https://doi.org/10. 4161/cc.26130 google scholar
  • Leontieva, O. V., Gudkov, A. V., & Blagosklonny, M. V. (2010). Weak p53 permits senes- cence during cell cycle arrest. Cell Cycle, 9(21), 4323-4327. https://doi.org/10. 4161/cc.9.21.13584 google scholar
  • Lessard, F., Igelmann, S., Trahan, C., Huot, G., Saint-Germain, E., Mignacca, L., Del Toro, N., Lopes-Paciencia, S., Le Calvé, B., Montero, M., Deschênes-Simard, X., Bury, M., Moiseeva, O., Rowell, M.-C., Zorca, C. E., Zenklusen, D., Brakier-Gingras, L., Bourdeau, V., Oeffinger, M., & Ferbeyre, G. (2018). Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway. Nature Cell Biology, 20(7), 789-799. https://doi.org/10.1038/s41556- 018-0127-y google scholar
  • Li, M., Yang, J., Liu, K., Yang, J., Zhan, X., Wang, L., Shen, X., Chen, J., & Mao, Z. (2020). p16 promotes proliferation in cervical carcinoma cells through CDK6-HuR-IL1A axis. Journal of Cancer, 11(6), 1457-1467. https://doi.org/10.7150/jca.35479 google scholar
  • Li, P., Pu, S., Lin, C., He, L., Zhao, H., Yang, C., Guo, Z., Xu, S., & Zhou, Z. (2022). Curcumin selectively induces colon cancer cell apoptosis and S cell cycle arrest by regulates Rb/E2F/p53 pathway. Journal of Molecular Structure, 1263, 133180. https://doi.org/10.1016/j.molstruc.2022.133180 google scholar
  • Li, Y., Nichols, M. A., Shay, J. W., & Xiong, Y. (1994). Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma suscep- tibility gene product pRb. Cancer Research, 54(23), 6078-6082. Retrieved from https://pubmed.ncbi.nlm.nih.gov/7954450/ google scholar
  • Liang, Y., Liang, N., Ma, Y., Tang, S., Ye, S., & Xiao, F. (2021). Role of Clusterin/NF-κB in the secretion of senescence-associated secretory phenotype in Cr (VI)-induced premature senescent L-02 hepatocytes. Ecotoxicology and Environmental Safety, 219, 112343. https://doi.org/10.1016/j.ecoenv.2021.112343 google scholar
  • Lin, C., Li, H., Liu, J., Hu, Q., Zhang, S., Zhang, N., Liu, L., Dai, Y., Cao, D., Li, X., Huang, B., Lu, J., & Zhang, Y. (2020). Arginine hypomethylation-mediated proteasomal degradation of histone H4—an early biomarker of cellular senescence. Cell Death & Differentiation, 27(9), 2697-2709. https://doi.org/10.1038/s41418-020- 0562-8 google scholar
  • Lisek, K., Campaner, E., Ciani, Y., Walerych, D., & Del Sal, G. (2018). Mutant p53 tunes the NRF2-dependent antioxidant response to support survival of cancer cells. Oncotarget, 9(29), 20508. https://doi.org/10.18632/oncotarget.24974 google scholar
  • Lisek, K., Walerych, D., & Del Sal, G. (2017). Mutant p53–Nrf2 axis regulates the proteasome machinery in cancer. Molecular & Cellular Oncology, 4(1), e1217967. https://doi.org/10.1080/23723556.2016.1217967 google scholar
  • Liu, G. Y., & Sabatini, D. M. (2020). mTOR at the nexus of nutrition, growth, ageing and disease. Nature reviews Molecular Cell Biology, 21(4), 183-203. https://doi.org/ 10.1038/s41580-019-0199-y google scholar
  • Liu, M., Casimiro, M. C., Wang, C., Shirley, L. A., Jiao, X., Katiyar, S., Ju, X., Li, Z., Yu, Z., Zhou, J., Johnson, M., Fortina, P., Hyslop, T., Windle, J. J., & Pestell, R. G. (2009). p21CIP1 attenuates Ras-and c-Myc-dependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo. Proceedings of the National Academy of Sciences, 106(45), 19035-19039. https://doi.org/10. 1073/pnas.0910009106 google scholar
  • Liu, Z., Lin, H., Gan, Y., Cui, C., Zhang, B., Gu, L., Zhou, J., Zhu, G., & Deng, D. (2019). P16 methylation leads to paclitaxel resistance of advanced non-small cell lung cancer. Journal of Cancer, 10(7), 1726-1733. https://doi.org/10.7150/jca.26482 google scholar
  • Liu, Z., Sun, M., Lu, K., Liu, J., Zhang, M., Wu, W., De, W., Wang, Z., & Wang, R. (2013). The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21WAF1/CIP1 expression. PloS One, 8(10), e77293. https://doi.org/10.1371/journal.pone.0077293 google scholar
  • Loewith, R., Jacinto, E., Wullschleger, S., Lorberg, A., Crespo, J. L., Bonenfant, D., Oppliger, W., Jenoe, P., & Hall, M. N. (2002). Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Molecular Cell, 10(3), 457-468. https://doi.org/10.1016/S1097-2765(02)00636-6 google scholar
  • Lord, C. J., & Ashworth, A. (2012). The DNA damage response and cancer therapy. Nature, 481(7381), 287-294. https://doi.org/10.1038/nature10760 google scholar
  • Lossaint, G., Horvat, A., Gire, V., Bačević, K., Mrouj, K., Charrier-Savournin, F., Georget, V., Fisher, D., & Dulić, V. (2022). Reciprocal regulation of p21 and Chk1 controls the cyclin D1-RB pathway to mediate senescence onset after G2 arrest. Journal of cell Science, 135(8), jcs259114. https://doi.org/10.1242/jcs.259114 google scholar
  • Ma, Z., Cai, Y., & Tian, C. (2023). ZWINT promotes the proliferation, migration, and invasion of cervical cancer cells by regulating the p53/p21 signaling pathway. Journal of Physiology Investigation, 66(5), 372-378. https://doi.org/10. 4103/cjop.cjop-d-23-00001 google scholar
  • Maddison, L. A., Sutherland, B. W., Barrios, R. J., & Greenberg, N. M. (2004). Conditional deletion of Rb causes early stage prostate cancer. Cancer Research, 64(17), 6018-6025. https://doi.org/10.1158/0008-5472.CAN-03-2509 google scholar
  • Maiuthed, A., Ninsontia, C., Erlenbach-Wuensch, K., Ndreshkjana, B., Muenzner, J. K., Caliskan, A., Ahmed, H. P., Chaotham, C., Hartmann, A., Vial Roehe, A., Mahadevan, V., Chanvorachote, P., & Schneider-Stock, R. (2018). Cytoplasmic p21 mediates 5-fluorouracil resistance by inhibiting pro-apoptotic Chk2. Cancers, 10(10), 373. https://doi.org/10.3390/cancers10100373 google scholar
  • Mak, V. C., Li, X., Rao, L., Zhou, Y., Tsao, S. W., & Cheung, L. W. (2021). p85β alters response to EGFR inhibitor in ovarian cancer through p38 MAPK-mediated regulation of DNA repair. Neoplasia, 23(7), 718-730. https://doi.org/10.1016/j.neo.2021.05.009 google scholar
  • Maki, C. G. (2010). Decision-making by p53 and mTOR. Aging (Albany NY), 2(6), 324-326. https://doi.org/10.18632/aging.100166 google scholar
  • Mandigo, A. C., Yuan, W., Xu, K., Gallagher, P., Pang, A., Guan, Y. F., Shafi, A. A., Thangavel, C., Sheehan, B., Bogdan, D., Paschalis, A., McCann, J. J., Laufer, T. S., Gordon, N., Vasilevskaya, I. A., Dylgjeri, E., Chand, S. N., Schiewer, M. J., Domingo-Domenech, J., … & Knudsen, K. E. (2021). RB/E2F1 as a master regulator of cancer cell metabolism in advanced disease. Cancer Discovery, 11(9), 2334-2353. https:// doi.org/10.1158/2159-8290.CD-20-1114 google scholar
  • Mansilla, S. F., De La Vega, M. B., Calzetta, N. L., Siri, S. O., & Gottifredi, V. (2020). CDK-independent and PCNA-dependent functions of p21 in DNA repli- cation. Genes, 11(6), 593. https://doi.org/10.3390/genes11060593 google scholar
  • Marusyk, A., Tabassum, D. P., Altrock, P. M., Almendro, V., Michor, F., & Polyak, K. (2014). Non-cell-autonomous driving of tumour growth supports sub-clonal hetero- geneity. Nature, 514(7520), 54-58. https://doi.org/10.1038/nature13556 google scholar
  • Maskey, R. S., Wang, F., Lehman, E., Wang, Y., Emmanuel, N., Zhong, W., Jin, G., Abraham, R. T., Arndt, K. T., Myers, J. S., & Mazurek, A. (2021). Sustained mTORC1 activity during palbociclib-induced growth arrest triggers senescence in ER+ breast cancer cells. Cell Cycle, 20(1), 65-80. https://doi.org/10.1080/15384101. 2020.1859195 google scholar
  • McNair, C., Xu, K., Mandigo, A. C., Benelli, M., Leiby, B., Rodrigues, D., Lindberg, J., Gron- berg, H., Crespo, M., De Laere, B., Dirix, L., Visakorpi, T., Li, F., Feng, F. Y., de Bono, J., Demichelis, F., Rubin, M. A., Brown, M., & Knudsen, K. E. (2018). Differential impact of RB status on E2F1 reprogramming in human cancer. The Journal of Clinical Investigation, 128(1), 341-358. https://doi.org/10.1172/JCI93566 google scholar
  • Mihara, M., Erster, S., Zaika, A., Petrenko, O., Chittenden, T., Pancoska, P., & Moll, U. M. (2003). p53 has a direct apoptogenic role at the mitochondria. Molecular Cell, 11(3), 577-590. https://doi.org/10.1016/S1097-2765(03)00050-9 google scholar
  • Milanovic, M., Yu, Y., & Schmitt, C. A. (2018). The senescence–stemness alliance–a can- cer-hijacked regeneration principle. Trends in Cell Biology, 28(12), 1049-1061. https://doi.org/10.1016/j.tcb.2018.09.001 google scholar
  • Moiseeva, O., Deschênes-Simard, X., St-Germain, E., Igelmann, S., Huot, G., Cadar, A. E., Bourdeau, V., Pollak, M. N., & Ferbeyre, G. (2013). Metformin inhibits the senescence‐associated secretory phenotype by interfering with IKK/NF‐κ B activation. Aging Cell, 12(3), 489-498. https://doi.org/10.1111/acel.12075 google scholar
  • Momtaz, S., Baeeri, M., Rahimifard, M., Haghi‐Aminjan, H., Hassani, S., & Abdollahi, M. (2019). Manipulation of molecular pathways and senescence hallmarks by natural compounds in fibroblast cells. Journal of Cellular Biochemistry, 120(4), 6209-6222. https://doi.org/10.1002/jcb.27909 google scholar
  • Mondal, P., Mohapatra, S., Bhunia, D., Gharai, P. K., Mukherjee, N., Gupta, V., Ghosh, S., & Ghosh, S. (2022). Designed hybrid anticancer nuclear-localized peptide inhibits aggressive cancer cell proliferation. RSC Medicinal Chemistry, 13(2), 196-201. https://doi.org/10.1039/D1MD00324K google scholar
  • Morgunova, G. V., Kolesnikov, A. V., Klebanov, A. A., & Khokhlov, A. N. (2015). Senes- cence-associated β-galactosidase—A biomarker of aging, DNA damage, or cell proliferation restriction?. Moscow University Biological Sciences Bulletin, 70, 165-167. https://doi.org/10.3103/S0096392515040082 google scholar
  • Moss, S. C., Lightell, D. J., Marx, S. O., Marks, A. R., & Woods, T. C. (2010). Rapamycin reg- ulates endothelial cell migration through regulation of the cyclin-dependent kinase inhibitor p27Kip1. Journal of Biological Chemistry, 285(16), 11991-11997. https://doi.org/10.1074/jbc.M109.066621 google scholar
  • Mossmann, D., Park, S., & Hall, M. N. (2018). mTOR signalling and cellular metabolism are mutual determinants in cancer. Nature Reviews Cancer, 18(12), 744-757. https://doi.org/10.1038/s41568-018-0074-8 google scholar
  • Mosteiro, L., Pantoja, C., de Martino, A., & Serrano, M. (2018). Senescence promotes in vivo reprogramming through p16 INK 4a and IL‐6. Aging Cell, 17(2), e12711. https://doi.org/10.1111/acel.12711 google scholar
  • Mrouj, K., Andrés-Sánchez, N., Dubra, G., Singh, P., Sobecki, M., Chahar, D., Al Ghoul, E., Aznar, A. B., Prieto, S., Pirot, N., Bernex, F., Bordignon, B., Hassen-Khodja, C., Villalba, M., Krasinska, L., & Fisher, D. (2021). Ki-67 regulates global gene expression and promotes sequential stages of carcinogenesis. Proceedings of the National Academy of Sciences, 118(10), e2026507118. https://doi.org/10. 1073/pnas.2026507118 google scholar
  • Munro, S., Carr, S. M., & La Thangue, N. B. (2012). Diversity within the pRb pathway: is there a code of conduct?. Oncogene, 31(40), 4343-4352. https://doi.org/10. 1038/onc.2011.603 google scholar
  • Nagahara, H., Vocero-Akbani, A. M., Snyder, E. L., Ho, A., Latham, D. G., Lissy, N. A., Becker-Hapak, M., Ezhevsky, S. A., & Dowdy, S. F. (1998). Transduction of full- length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration. Nature Medicine, 4(12), 1449-1452. https://doi.org/10.1038/4042 google scholar
  • Narita, M., Nuñez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., & Lowe, S. W. (2003). Rb-mediated heterochromatin formation and google scholar
  • silencing of E2F target genes during cellular senescence. Cell, 113(6), 703-716. https://doi.org/10.1016/S0092-8674(03)00401-X google scholar
  • Niederst, M. J., Sequist, L. V., Poirier, J. T., Mermel, C. H., Lockerman, E. L., Garcia, A. R., Katayama, R., Costa, C., Ross, K. N., Moran, T., Howe, E., Fulton, L. E., Mulvey, H. E., Bernardo, L. A., Mohamoud, F., Miyoshi, N., VanderLaan, P. A., Costa, D. B., Jänne, P. A., & Engelman, J. A. (2015). RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nature Communications, 6(1), 6377. https://doi.org/10.1038/ncomms7377 google scholar
  • Nilsson, M. B., Langley, R. R., & Fidler, I. J. (2005). Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Research, 65(23), 10794-10800. https://doi.org/10.1158/0008-5472.CAN-05-0623 google scholar
  • Niu, L. L., Cheng, C. L., Li, M. Y., Yang, S. L., Hu, B. G., Chong, C. C., Chan, S. L., Ren, J., Chen, G. G., & Lai, P. B. S. (2018). ID1-induced p16/IL6 axis activation contributes to the resistant of hepatocellular carcinoma cells to sorafenib. Cell Death & Disease, 9(9), 852. https://doi.org/10.1038/s41419-018-0926-x google scholar
  • Nowosad, A., Jeannot, P., Callot, C., Creff, J., Perchey, R. T., Joffre, C., Codogno, P., Manenti, S., & Besson, A. (2020). p27 controls Ragulator and mTOR activity in amino acid- deprived cells to regulate the autophagy–lysosomal pathway and coordinate cell cycle and cell growth. Nature Cell Biology, 22(9), 1076-1090. https://doi. org/10.1038/s41556-020-0554-4 google scholar
  • Ohtani, N. (2022). The roles and mechanisms of senescence-associated secretory phenotype (SASP): can it be controlled by senolysis?. Inflammation and Regeneration, 42(1), 11. https://doi.org/10.1186/s41232-022-00197-8 google scholar
  • Okuma, A., Hanyu, A., Watanabe, S., & Hara, E. (2017). p16Ink4a and p21Cip1/ Waf1 promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis. Nature Communications, 8(1), 2050. https://doi.org/10.1038/ s41467-017-02281-x google scholar
  • Olszewska, A., Borkowska, A., Granica, M., Karolczak, J., Zglinicki, B., Kieda, C., & Was, H. (2022). Escape from cisplatin-induced senescence of hypoxic lung cancer cells can be overcome by hydroxychloroquine. Frontiers in Oncology, 11, 738385. https://doi.org/10.3389/fonc.2021.738385 google scholar
  • Pack, L. R., Daigh, L. H., & Meyer, T. (2019). Putting the brakes on the cell cycle: mecha- nisms of cellular growth arrest. Current Opinion in Cell Biology, 60, 106-113. https://doi.org/10.1016/j.ceb.2019.05.005 google scholar
  • Palafox, M., Monserrat, L., Bellet, M., Villacampa, G., Gonzalez-Perez, A., Oliveira, M., Brasó-Maristany, F., Ibrahimi, N., Kannan, S., Mina, L., Herrera-Abreu, M. T., Òdena, A., Sánchez-Guixé, M., Capelán, M., Azaro, A., Bruna, A., Rodríguez, O., Guzmán, M., Grueso, J., … & Serra, V. (2022). High p16 expression and heterozy- gous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer. Nature Communications, 13(1), 5258. https://doi.org/10.1038/s41467- 022-32828-6 google scholar
  • Pang, X., Gao, S., Liu, T., Xu, F. X., Fan, C., Zhang, J. F., & Jiang, H. (2024). Identification of STAT3 as a biomarker for cellular senescence in liver fibrosis: A bioinformatics and experimental validation study. Genomics, 116(2), 110800. https://doi.org/ 10.1016/j.ygeno.2024.110800 google scholar
  • Park, S. Y., & Nam, J. S. (2020). The force awakens: metastatic dormant cancer cells. Experimental & Molecular Medicine, 52(4), 569-581. https://doi.org/10. 1038/s12276-020-0423-z google scholar
  • Passos, J. F., Nelson, G., Wang, C., Richter, T., Simillion, C., Proctor, C. J., Miwa, S., Olijs- lagers, S., Hallinan, J., Wipat, A., Saretzki, G., Rudolph, K. L., Kirkwood, T. B. L., & von Zglinicki, T. (2010). Feedback between p21 and reactive oxygen production is necessary for cell senescence. Molecular Systems Biology, 6(1), 347. https:// doi.org/10.1038/msb.2010.5 google scholar
  • Piechota, M., Sunderland, P., Wysocka, A., Nalberczak, M., Sliwinska, M. A., Radwanska, K., & Sikora, E. (2016). Is senescence-associated β-galactosidase a marker of neuronal senescence?. Oncotarget, 7(49), 81099-81109. https://doi.org/10. 18632/oncotarget.12752 google scholar
  • Pietsch, E. C., Perchiniak, E., Canutescu, A. A., Wang, G., Dunbrack, R. L., & Murphy, M. E. (2008). Oligomerization of BAK by p53 utilizes conserved residues of the p53 DNA binding domain. Journal of Biological Chemistry, 283(30), 21294-21304. https://doi.org/10.1074/jbc.M710539200 google scholar
  • Puri, P. L., Wu, Z., Zhang, P., Wood, L. D., Bhakta, K. S., Han, J., Feramisco, J. R., Karin, M., & Wang, J. Y. J. (2000). Induction of terminal differentiation by constitutive activation of p38 MAP kinase in human rhabdomyosarcoma cells. Genes & development, 14(5), 574-584. Retrieved from https://pubmed.ncbi.nlm.nih.gov/ 10716945/ google scholar
  • Rajendran, P., Alzahrani, A. M., Hanieh, H. N., Kumar, S. A., Ben Ammar, R., Rengarajan, T., & Alhoot, M. A. (2019). Autophagy and senescence: A new insight in selected human diseases. Journal of Cellular Physiology, 234(12), 21485-21492. https:// doi.org/10.1002/jcp.28895 google scholar
  • Rayess, H., Wang, M. B., & Srivatsan, E. S. (2012). Cellular senescence and tumor suppressor gene p16. International Journal of Cancer, 130(8), 1715-1725. https:// doi.org/10.1002/ijc.27316 google scholar
  • Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., Sansom, O. J., Zender, L., & Keyes, W. M. (2017). The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & Development, 31(2), 172-183. https://doi.org/10.1101/gad.290635.116 google scholar
  • Rodier, F., Coppé, J.-P., Patil, C. K., Hoeijmakers, W. A. M., Muñoz, D. P., Raza, S. R., Freund, A., Campeau, E., Davalos, A. R., & Campisi, J. (2009). Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine se- cretion. Nature Cell Biology, 11(8), 973-979. https://doi.org/10.1038/ncb1909 google scholar
  • Rodier, F., Muñoz, D. P., Teachenor, R., Chu, V., Le, O., Bhaumik, D., Coppé, J.-P., Campeau, E., Beauséjour, C. M., Kim, S.-H., Davalos, A. R., & Campisi, J. (2011). DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. Journal of Cell Science, 124(1), 68-81. https://doi.org/10.1242/jcs.071340 google scholar
  • Ruefli, A. A., & Johnstone, R. W. (2003). A role for P-glycoprotein in regulating cell growth and survival. Clinical and Applied Immunology Reviews, 4(1), 31-47. https://doi.org/10.1016/S1529-1049(03)00005-9 google scholar
  • Ruhland, M. K., Loza, A. J., Capietto, A.-H., Luo, X., Knolhoff, B. L., Flanagan, K. C., Belt, B. A., Alspach, E., Leahy, K., Luo, J., Schaffer, A., Edwards, J. R., Longmore, G., Faccio, R., DeNardo, D. G., & Stewart, S. A. (2016). Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nature Communications, 7(1), 11762. https://doi.org/10.1038/ncomms11762 google scholar
  • Sadaie, M., Salama, R., Carroll, T., Tomimatsu, K., Chandra, T., Young, A. R. J., Narita, M., Pérez-Mancera, P. A., Bennett, D. C., Chong, H., Kimura, H., & Narita, M. (2013). Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence. Genes & Development, 27(16), 1800-1808. https://doi.org/10.1101/gad.217281.113 google scholar
  • Sagiv, A., Burton, D. G. A., Moshayev, Z., Vadai, E., Wensveen, F., Ben-Dor, S., Golani, O., Polic, B., & Krizhanovsky, V. (2016). NKG2D ligands mediate immunosurveillance of senescent cells. Aging (Albany NY), 8(2), 328-344. https://doi.org/10.18632/ aging.100897 google scholar
  • Schulz-Heddergott, R., Stark, N., Edmunds, S. J., Li, J., Conradi, L.-C., Bohnenberger, H., Ceteci, F., Greten, F. R., Dobbelstein, M., & Moll, U. M. (2018). Therapeutic ablation of gain-of-function mutant p53 in colorectal cancer inhibits Stat3- mediated tumor growth and invasion. Cancer Cell, 34(2), 298-314. https://doi. org/10.1016/j.ccell.2018.07.004 google scholar
  • Selvam, S. P., Roth, B. M., Nganga, R., Kim, J., Cooley, M. A., Helke, K., Smith, C. D., & Ogretmen, B. (2018). Balance between senescence and apoptosis is regulated by telomere damage–induced association between p16 and caspase-3. Journal of Biological Chemistry, 293(25), 9784-9800. https://doi.org/10.1074/jbc.RA118. 003506 google scholar
  • Sharma, R., & Padwad, Y. (2019). In search of nutritional anti-aging targets: TOR inhibitors, SASP modulators, and BCL-2 family suppressors. Nutrition, 65, 33-38. https://doi.org/10.1016/j.nut.2019.01.020 google scholar
  • Sheekey, E., & Narita, M. (2023). p53 in senescence–it's a marathon, not a sprint. The FEBS journal, 290(5), 1212-1220. https://doi.org/10.1111/febs.16325 google scholar
  • Sherr, C. J., & Roberts, J. M. (1999). CDK inhibitors: positive and negative regulators of G1-phase progression. Genes & development, 13(12), 1501-1512. Retrieved from https://pubmed.ncbi.nlm.nih.gov/10385618/ google scholar
  • Shin, E., Jung, W. H., & Koo, J. S. (2015). Expression of p16 and pRB in invasive breast cancer. International Journal of Clinical and Experimental Pathology, 8(7), 8209-8217. Retrieved from https://pmc.ncbi.nlm.nih.gov/articles/PMC4555717/ google scholar
  • Slingerland, J., & Pagano, M. (2000). Regulation of the cdk inhibitor p27 and its deregulation in cancer. Journal of Cellular Physiology, 183(1), 10-17. https://doi. org/10.1002/(sici)1097-4652(200004)183:1%3C10::aid-jcp2%3E3.0.co;2-i google scholar
  • Slobodnyuk, K., Radic, N., Ivanova, S., Llado, A., Trempolec, N., Zorzano, A., & Nebreda, A. R. (2019). Autophagy-induced senescence is regulated by p38α signaling. Cell Death & Disease, 10(6), 376. https://doi.org/10.1038/s41419-019-1607-0 google scholar
  • Sobecki, M., Mrouj, K., Camasses, A., Parisis, N., Nicolas, E., Lle` res, D., Gerbe, F., Prieto, S., Krasinska, L., David, A., Eguren, M., Birling, M.-C., Urbach, S., Hem, S., De´ jardin, J., Malumbres, M., Jay, P., Dulic, V., Lafontaine, D. L. J., … & Fisher, D. (2016). The cell proliferation antigen Ki-67 organises heterochromatin. Elife, 5, e13722. https://doi.org/10.7554/eLife.13722 google scholar
  • Sobecki, M., Mrouj, K., Colinge, J., Gerbe, F., Jay, P., Krasinska, L., Dulic, V., & Fisher, D. (2017). Cell-cycle regulation accounts for variability in Ki-67 expression levels. Cancer Research, 77(10), 2722-2734. https://doi.org/10.1158/0008-5472. CAN-16-0707 google scholar
  • Sousa-Victor, P., Gutarra, S., García-Prat, L., Rodriguez-Ubreva, J., Ortet, L., Ruiz-Bonilla, V., Jardí, M., Ballestar, E., González, S., Serrano, A. L., Perdiguero, E., & Muñoz- Cánoves, P. (2014). Geriatric muscle stem cells switch reversible quiescence into senescence. Nature, 506(7488), 316-321. https://doi.org/10.1038/nature 13013 google scholar
  • Storer, M., Mas, A., Robert-Moreno, A., Pecoraro, M., Ortells, M. C., Di Giacomo, V., Yosef, R., Pilpel, N., Krizhanovsky, V., Sharpe, J., & Keyes, W. M. (2013). Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell, 155(5), 1119-1130. https://doi.org/10.1016/j.cell.2013.10.041 google scholar
  • Suda, M., Shimizu, I., Katsuumi, G., Hsiao, C. L., Yoshida, Y., Matsumoto, N., Yoshida, Y., Katayama, A., Wada, J., Seki, M., Suzuki, Y., Okuda, S., Ozaki, K., Nakanishi-Matsui, M., & Minamino, T. (2022). Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Scientific Reports, 12(1), 6522. https://doi.org/10.1038/s41598-022-10522-3 google scholar
  • Sun, H., Wang, H., Wang, X., Aoki, Y., Wang, X., Yang, Y., Cheng, X., Wang, Z., & Wang, X. (2020). Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Theranostics, 10(15), 6928-6945. https:// doi.org/10.7150/thno.43811 google scholar
  • Sun, X., Bizhanova, A., Matheson, T. D., Yu, J., Zhu, L. J., & Kaufman, P. D. (2017). Ki-67 contributes to normal cell cycle progression and inactive X heterochromatin in p21 checkpoint-proficient human cells. Molecular and cellular biology, 37(17), e00569-16. https://doi.org/10.1128/mcb.00569-16 google scholar
  • Sun, Z., Chen, H., & Liu, Y. (2023). Influence of Oxa-Nano-Liposome on the Drug Resistance of Gastric Cancer Cells Under p53-Mediated Autophagy. Science of Advanced Materials, 15(11), 1525-1533. https://doi.org/10.1166/sam.2023.4544 google scholar
  • Swanson, E. C., Manning, B., Zhang, H., & Lawrence, J. B. (2013). Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence. Journal of Cell Biology, 203(6), 929-942. https://doi.org/10.1083/ jcb.201306073 google scholar
  • Swat, A., Dolado, I., Rojas, J. M., & Nebreda, A. R. (2009). Cell density-dependent inhibition of epidermal growth factor receptor signaling by p38α mitogen- activated protein kinase via Sprouty2 downregulation. Molecular and Cellular Biology, 29(12), 3332-3343. https://doi.org/10.1128/MCB.01955-08 google scholar
  • Tanaka, T., Narazaki, M., & Kishimoto, T. (2014). IL-6 in inflammation, immunity, and disease. Cold Spring Harbor Perspectives in Biology, 6(10), a016295. https:// doi.org/10.1101/cshperspect.a016295 google scholar
  • Tang, H., Fan, X., Xing, J., Liu, Z., Jiang, B., Dou, Y., Gorospe, M., & Wang, W. (2015). NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation. Aging (Albany NY), 7(12), 1143-1155. https://doi.org/ 10.18632/aging.100860 google scholar
  • Tang, Y., Zhao, W., Chen, Y., Zhao, Y., & Gu, W. (2008). Acetylation is indispensable for p53 activation. Cell, 133(4), 612-626. https://doi.org/10.1016/j.cell.2008.03.025 google scholar
  • Teo, Y. V., Rattanavirotkul, N., Olova, N., Salzano, A., Quintanilla, A., Tarrats, N., Kiourtis, C., Müller, M., Green, A. R., Adams, P. D., Acosta, J.-C., Bird, T. G., Kirschner, K., Neretti, N., & Chandra, T. (2019). Notch signaling mediates secondary senes- cence. Cell Reports, 27(4), 997-1007. https://doi.org/10.1016/j.celrep.2019.03.104 google scholar
  • Terzi, M. Y., Izmirli, M., & Gogebakan, B. (2016). The cell fate: senescence or quies- cence. Molecular Biology Reports, 43, 1213-1220. http://dx.doi.org/10.1007%2Fs 11033-016-4065-0 google scholar
  • Thangavel, C., Boopathi, E., Liu, Y., McNair, C., Haber, A., Perepelyuk, M., Bhardwaj, A., Addya, S., Ertel, A., Shoyele, S., Birbe, R., Salvino, J. M., Dicker, A. P., Knudsen, K. google scholar
  • E., & Den, R. B. (2018). Therapeutic challenge with a CDK 4/6 inhibitor induces an RB-dependent SMAC-mediated apoptotic response in non–small cell lung cancer. Clinical Cancer Research, 24(6), 1402-1414. https://doi.org/10.1158/1078- 0432.CCR-17-2074 google scholar
  • Thangavel, C., Dean, J. L., Ertel, A., Knudsen, K. E., Aldaz, C. M., Witkiewicz, A. K., Clarke, R., & Knudsen, E. S. (2011). Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocrine-related Cancer, 18(3), 333-345. https://doi.org/10.1530/ERC-10-0262 google scholar
  • Thoms, H. C., Dunlop, M. G., & Stark, L. A. (2007). p38-mediated inactivation of cyclin D1/cyclin-dependent kinase 4 stimulates nucleolar translocation of RelA and apoptosis in colorectal cancer cells. Cancer Research, 67(4), 1660-1669. https:// doi.org/10.1158/0008-5472.CAN-06-1038 google scholar
  • Tonnessen-Murray, C. A., Frey, W. D., Rao, S. G., Shahbandi, A., Ungerleider, N. A., Olayiwola, J. O., Murray, L. B., Vinson, B. T., Chrisey, D. B., Lord, C. J., & Jackson, J. G. (2019). Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival. Journal of Cell Biology, 218(11), 3827-3844. https://doi. org/10.1083/jcb.201904051 google scholar
  • Triana-Martínez, F., Loza, M. I., & Domínguez, E. (2020). Beyond tumor suppression: senescence in cancer stemness and tumor dormancy. Cells, 9(2), 346. https:// doi.org/10.3390/cells9020346 google scholar
  • Truskowski, K., Amend, S. R., & Pienta, K. J. (2023). Dormant cancer cells: programmed quiescence, senescence, or both?. Cancer and Metastasis Reviews, 42(1), 37-47. https://doi.org/10.1007/s10555-022-10073-z google scholar
  • Valieva, Y., Ivanova, E., Fayzullin, A., Kurkov, A., & Igrunkova, A. (2022). Senescence- associated β-galactosidase detection in pathology. Diagnostics, 12(10), 2309. https://doi.org/10.3390/diagnostics12102309 google scholar
  • van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446. https://doi.org/10.1038/nature13193 google scholar
  • Vilgelm, A. E., Johnson, C. A., Prasad, N., Yang, J., Chen, S.-C., Ayers, G. D., Pawlikowski, J. S., Raman, D., Sosman, J. A., Kelley, M., Ecsedy, J. A., Shyr, Y., Levy, S. E., & Richmond, A. (2016). Connecting the dots: therapy-induced senescence and a tumor-suppressive immune microenvironment. Journal of the National Cancer Institute, 108(6), djv406. https://doi.org/10.1093/jnci/djv406 google scholar
  • Wagner, J., Damaschke, N., Yang, B., Truong, M., Guenther, C., McCormick, J., Huang, W., & Jarrard, D. (2015). Overexpression of the novel senescence marker β- galactosidase (GLB1) in prostate cancer predicts reduced PSA recurrence. PloS One, 10(4), e0124366. https://doi.org/10.1371/journal.pone.0124366 google scholar
  • Wakita, M., Takahashi, A., Sano, O., Loo, T. M., Imai, Y., Narukawa, M., Iwata, H., Matsu- daira, T., Kawamoto, S., Ohtani, N., Yoshimori, T., & Hara, E. (2020). A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells. Nature Communications, 11(1), 1935. https://doi.org/10.1038/s 41467-020-15719-6 google scholar
  • Wander, S. A., Zhao, D., Besser, A. H., Hong, F., Wei, J., Ince, T. A., Milikowski, C., Bish- opric, N. H., Minn, A. J., Creighton, C. J., & Slingerland, J. M. (2013). PI3K/mTOR inhibition can impair tumor invasion and metastasis in vivo despite a lack of antiproliferative action in vitro: implications for targeted therapy. Breast Cancer Research and Treatment, 138, 369-381. https://doi.org/10.1007/s10549- 012-2389-6 google scholar
  • Wang, B., Varela-Eirin, M., Brandenburg, S. M., Hernandez-Segura, A., van Vliet, T., Jongbloed, E. M., Wilting, S. M., Ohtani, N., Jager, A., & Demaria, M. (2020). Phar- macological CDK4/6 inhibition unravels a p53-induced secretory phenotype in senescent cells. bioRxiv. https://doi.org/10.1101/2020.06.05.135715 google scholar
  • Wang, H., Grand, R. J., Milner, A. E., Armitage, R. J., Gordon, J., & Gregory, C. D. (1996). Re- pression of apoptosis in human B-lymphoma cells by CD40-ligand and Bcl-2: relationship to the cell-cycle and role of the retinoblastoma protein. Oncogene, 13(2), 373-379. Retrieved from https://pubmed.ncbi.nlm.nih.gov/8710376/ google scholar
  • Wang, H., Zhu, L. J., Yang, Y. C., Wang, Z. X., & Wang, R. (2014). MiR-224 promotes the chemoresistance of human lung adenocarcinoma cells to cisplatin via regulating G1/S transition and apoptosis by targeting p21WAF1/CIP1. British Journal of Cancer, 111(2), 339-354. https://doi.org/10.1038/bjc.2014.157 google scholar
  • Wang, L., Lankhorst, L., & Bernards, R. (2022). Exploiting senescence for the treatment of cancer. Nature Reviews Cancer, 22(6), 340-355. https://doi.org/10.1038/s 41568-022-00450-9 google scholar
  • Wang, R. H., Liu, C. W., Avramis, V. I., & Berndt, N. (2001). Protein phosphatase 1α- mediated stimulation of apoptosis is associated with dephosphorylation of the retinoblastoma protein. Oncogene, 20(43), 6111-6122. https://doi.org/10. 1038/sj.onc.1204829 google scholar
  • Wang, Z., Zhan, Y., Xu, J., Wang, Y., Sun, M., Chen, J., Liang, T., Wu, L., & Xu, K. (2020). β-sitosterol reverses multidrug resistance via BCRP suppression by inhibiting the p53–MDM2 interaction in colorectal cancer. Journal of Agricultural and Food Chemistry, 68(12), 3850-3858. https://doi.org/10.1021/acs.jafc.0c00107 google scholar
  • Watanabe, A., Suzuki, H., Yokobori, T., Tsukagoshi, M., Altan, B., Kubo, N., Suzuki, S., Araki, K., Wada, S., Kashiwabara, K., Hosouchi, Y., & Kuwano, H. (2014). Stathmin1 regulates p27 expression, proliferation and drug resistance, resulting in poor clinical prognosis in cholangiocarcinoma. Cancer Science, 105(6), 690-696. https://doi.org/10.1111/cas.12417 google scholar
  • Webber, J. L., & Tooze, S. A. (2010). Coordinated regulation of autophagy by p38α MAPK through mAtg9 and p38IP. The EMBO Journal, 29(1), 27-40. https://doi.org/10. 1038/emboj.2009.321 google scholar
  • Witkiewicz, A. K., Chung, S., Brough, R., Vail, P., Franco, J., Lord, C. J., & Knudsen, E. S. (2018). Targeting the vulnerability of RB tumor suppressor loss in triple- negative breast cancer. Cell Reports, 22(5), 1185-1199. https://doi.org/10.1016/j. celrep.2018.01.022 google scholar
  • Wu, B., Ueno, M., Onodera, M., Kusaka, T., Huang, C.-l., Hosomi, N., Kanenishi, K., & Sakamoto, H. (2009). Age-related changes in P-glycoprotein expression in senescence-accelerated mouse. Current Aging Science, 2(3), 187-192. google scholar
  • Wu, M. F., Huang, Y. H., Chiu, L. Y., Cherng, S. H., Sheu, G. T., & Yang, T. Y. (2022). Curcumin induces apoptosis of chemoresistant lung cancer cells via ROS-regulated p38 MAPK phosphorylation. International Journal of Molecular Sciences, 23(15), 8248. https://doi.org/10.3390/ijms23158248 google scholar
  • Xiao, Y., Liang, M. R., Liu, C. C., Wang, Y. N., Zeng, Y., Zhou, J., Zhu, H.T., Wang, Q., Zou, Y., & Zeng, S. Y. (2019). Overexpression of P16 reversed the MDR1-mediated DDP resistance in the cervical adenocarcinoma by activating the ERK1/2 signaling pathway. Cell Division, 14, 1-10. https://doi.org/10.1186/s13008-019-0048-6 google scholar
  • Xu, B., Jia, Q., Liao, X., Fan, T., Mou, L., Song, Y., Zhu, C., Yang, T., Li, Z., Wang, M., Zhang, Q., & Liang, L. (2024). Inositol hexaphosphate enhances chemotherapy by reversing senescence induced by persistently activated PERK and diph- thamide modification of eEF2. Cancer Letters, 582, 216591. https://doi.org/10. 1016/j.canlet.2023.216591 google scholar
  • Xu, J., Shi, J., Tang, W., Jiang, P., Guo, M., Zhang, B., & Ma, G. (2020). ROR2 promotes the epithelial‐mesenchymal transition by regulating MAPK/p38 signaling pathway in breast cancer. Journal of Cellular Biochemistry, 121(10), 4142-4153. https:// doi.org/10.1002/jcb.29666 google scholar
  • Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon- Cardo, C., & Lowe, S. W. (2007). Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature, 445(7128), 656-660. https://doi.org/10.1038/nature05529 google scholar
  • Yang, H. W., Chung, M., Kudo, T., & Meyer, T. (2017). Competing memories of mitogen and p53 signalling control cell-cycle entry. Nature, 549(7672), 404-408. https:// doi.org/10.1038/nature23880 google scholar
  • Yao, J., Huang, A., Zheng, X., Liu, T., Lin, Z., Zhang, S., Yang, Q., Zhang, T., & Ma, H. (2017). 53BP1 loss induces chemoresistance of colorectal cancer cells to 5-fluorouracil by inhibiting the ATM–CHK2–P53 pathway. Journal of Cancer Research and Clinical Oncology, 143, 419-431. https://doi.org/10.1007/s00432-016-2302-5 google scholar
  • You, H., Yamamoto, K., & Mak, T. W. (2006). Regulation of transactivation-independent proapoptotic activity of p53 by FOXO3a. Proceedings of the National Academy of Sciences, 103(24), 9051-9056. https://doi.org/10.1073/pnas.0600889103 google scholar
  • Yu, D.-M., Jung, S. H., An, H.-T., Lee, S., Hong, J., Park, J. S., Lee, H., Lee, H., Bahn, M.-S., Lee, H. C., Han, N.-K., Ko, J., Lee, J.-S., & Ko, Y.-G. (2017). Caveolin‐1 defi- ciency induces premature senescence with mitochondrial dysfunction. Aging Cell, 16(4), 773-784. https://doi.org/10.1111/acel.12606 google scholar
  • Yu, W., Imoto, I., Inoue, J., Onda, M., Emi, M., & Inazawa, J. (2007). A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity. Oncogene, 26(8), 1178-1187. https://doi.org/10.1038/sj.onc. 1209899 google scholar
  • Yu, Y., Schleich, K., Yue, B., Ji, S., Lohneis, P., Kemper, K., Silvis, M. R., Qutob, N., van Rooijen, E., Werner-Klein, M., Li, L., Dhawan, D., Meierjohann, S., Reimann, M., google scholar
  • Elkahloun, A., Treitschke, S., Dörken, B., Speck, C., Mallette, F. A., … & Lee, S. (2018). Targeting the senescence-overriding cooperative activity of struc- turally unrelated H3K9 demethylases in melanoma. Cancer Cell, 33(2), 322-336. https://doi.org/10.1016/j.ccell.2018.01.002 google scholar
  • Yuan, B., El Dana, F., Ly, S., Yan, Y., Ruvolo, V., Shpall, E. J., Konopleva, M., Andreeff, M., & Battula, V. L. (2020a). Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance therapy resistance in AML through a TGF-β-p38-ALDH2 pathway. PLoS One, 15(11), e0242809. https://doi.org/10.1371/ journal.pone.0242809 google scholar
  • Yuan, X., Liu, Y., Bijonowski, B. M., Tsai, A.-C., Fu, Q., Logan, T. M., Ma, T., & Li, Y. (2020b). NAD+/NADH redox alterations reconfigure metabolism and rejuvenate senes- cent human mesenchymal stem cells in vitro. Communications Biology, 3(1), 774. https://doi.org/10.1038/s42003-020-01514-y google scholar
  • Zeng, C. Y., Yang, T. T., Zhou, H. J., Zhao, Y., Kuang, X., Duan, W., & Du, J. R. (2019). Lentiviral vector–mediated overexpression of Klotho in the brain improves Alzheimer's disease–like pathology and cognitive deficits in mice. Neurobiology of Aging, 78, 18-28. https://doi.org/10.1016/j.neurobiolaging.2019.02.003 google scholar
  • Zhang, H., Stallock, J. P., Ng, J. C., Reinhard, C., & Neufeld, T. P. (2000). Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes & development, 14(21), 2712-2724. https://doi.org/10.1101/gad.835000 google scholar
  • Zhao, G., Wang, H., Xu, C., Wang, P., Chen, J., Wang, P., Sun, Z., Su, Y., Wang, Z., Han, L., & Tong, T. (2016). SIRT6 delays cellular senescence by promoting p27Kip1 ubiqui- tin-proteasome degradation. Aging (Albany NY), 8(10), 2308-2323. https://doi. org/10.18632/aging.101038 google scholar
  • Zhao, S., Wang, L., Ouyang, M., Xing, S., Liu, S., Sun, L., & Yu, H. (2024). Polyploid giant cancer cells induced by Docetaxel exhibit a senescence phenotype with the expression of stem cell markers in ovarian cancer cells. Plos One, 19(7), e0306969. https://doi.org/10.1371/journal.pone.0306969 google scholar
  • Zhao, Y. F., Zhao, J. Y., Yue, H., Hu, K. S., Shen, H., Guo, Z. G., & Su, X. J. (2015). FOXD1 pro- motes breast cancer proliferation and chemotherapeutic drug resistance by targeting p27. Biochemical and Biophysical Research Communications, 456(1), 232-237. https://doi.org/10.1016/j.bbrc.2014.11.064 google scholar
  • Zhou, W., Wang, J., Qi, Q., Feng, Z., Huang, B., Chen, A., Zhang, D., Li, W., Zhang, Q., Bjerkvig, R., Li, X., & Wang, J. (2018). Matrine induces senescence of human glioblastoma cells through suppression of the IGF1/PI3K/AKT/p27 signaling pathway. Cancer Medicine, 7(9), 4729-4743. https://doi.org/10.1002/cam4.1720 google scholar

Current Biomarkers of Cellular Senescence: Mechanistic Insights and Their Implications for Drug Resistance in Cancer

Year 2025, Volume: 55 Issue: 2, 301 - 317, 23.09.2025
https://doi.org/10.26650/IstanbulJPharm.2025.1603560

Abstract

One of the major challenges in cancer treatment is intrinsic or acquired drug resistance. To overcome this resistance, various alternative therapeutic strategies have been explored. The induction of cellular senescence could enhance the chemosensitivity of cancer cells, thereby overcoming drug resistance. Cellular senescence, a form of cell cycle exit, is important for the development of promising new treatment approaches for cancer because of its irreversible nature. However, there are many contradictory outcomes of triggering the senescence program in cancer cells. Moreover, the accurate detection of cell senescence remains uncertain. Therefore, the biomarkers of cell senescence, driving the senescence program, and their roles in various cellular pathways are prominent to determine for targeting the key cellular network in molecular oncology. A range of biomarkers are used to detect senescent cells. The objective of this review is to provide a comprehensive mechanistic understanding of cellular senescence biomarkers by examining their potential contributions to carcinogenesis and chemoresistance. Understanding cellular states is a current issue in cancer studies and is important for correctly assessing the effectiveness of treatment. In this review, the relationships between chemotherapeutic resistance and senescent biomarkers are discussed in the context of studies conducted over the past decade. This knowledge is crucial for improving the identification of senescence, paving the way for developing targeted strategies to regulate the senescence for cancer therapy and drug resistance.

References

  • Acosta, J. C., O'Loghlen, A., Banito, A., Guijarro, M. V., Augert, A., Raguz, S., Fumagalli, M., Da Costa, M., Brown, C., Popov, N., Takatsu, Y., Melamed, J., d'Adda di Fagagna, F., Bernard, D., Hernando, E., Gil, J. (2008). Chemokine signaling via the CXCR2 receptor reinforces senescence. cell, 133(6), 1006-1018. https://doi.org/10.1016/ j.cell.2008.03.038 google scholar
  • Alessio, N., Aprile, D., Cappabianca, S., Peluso, G., Di Bernardo, G., & Galderisi, U. (2021). Different stages of quiescence, senescence, and cell stress identified by molecular algorithm based on the expression of Ki67, RPS6, and beta- galactosidase activity. International Journal of Molecular Sciences, 22(6), 3102. https://doi.org/10.3390/ijms22063102 google scholar
  • Alexander, K., & Hinds, P. W. (2001). Requirement for p27KIP1 in retinoblastoma pro- tein-mediated senescence. Molecular and Cellular Biology, 21(11), 3616-3631. https://doi.org/10.1128/MCB.21.11.3616-3631.2001 google scholar
  • Alimbetov, D., Davis, T., Brook, A. J., Cox, L. S., Faragher, R. G., Nurgozhin, T., Zhumadilov, Z., Kipling, D. (2016). Suppression of the senescence-associated secretory phenotype (SASP) in human fibroblasts using small molecule inhibitors of p38 MAP kinase and MK2. Biogerontology, 17, 305-315. https://doi.org/10.1007/ s10522-015-9610-z google scholar
  • Alspach, E., Flanagan, K. C., Luo, X., Ruhland, M. K., Huang, H., Pazolli, E., Donlin, M. J., Marsh, T., Piwnica-Worms, D., Monahan, J., Novack, D. V., McAllister, SS., Stewart, S.A. (2014). p38MAPK plays a crucial role in stromal-mediated tumori- genesis. Cancer discovery, 4(6), 716-729. https://doi.org/10.1158/2159-8290.CD- 13-0743 google scholar
  • Althubiti, M., Lezina, L., Carrera, S., Jukes-Jones, R., Giblett, S. M., Antonov, A., Barlev, N., Saldanha, G. S., Pritchard, C. A., Cain, K., Macip, S. (2014). Characterization of novel markers of senescence and their prognostic potential in cancer. Cell death & disease, 5(11), e1528-e1528. https://doi.org/10.1038/cddis.2014.489 google scholar
  • Amor, C., Feucht, J., Leibold, J., Ho, Y-J., Zhu, C., Alonso-Curbelo, D., Mansilla-Soto, J., Boyer, J. A., Li, X., Giavridis, T., Kulick, A., Houlihan, S., Peerschke, E., Friedman, S. L., Ponomarev, V., Piersigilli, A., Sadelain, M., Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. https://doi.org/10.1038/s41586-020-2403-9 google scholar
  • Aschauer, L., & Muller, P. A. (2016). Novel targets and interaction partners of mu- tant p53 Gain-Of-Function. Biochemical Society Transactions, 44(2), 460-466. https://doi.org/10.1042/BST20150261 google scholar
  • Azazmeh, N., Assouline, B., Winter, E., Ruppo, S., Nevo, Y., Maly, A., Meir, K., Witkiewicz, A. K., Cohen, J., Rizou, S. V., Pikarsky, E., Luxenburg, C., Gorgoulis, V. G., Ben-Porath, I. (2020). Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation. Nature communications, 11(1), 2711. https://doi.org/10.1038/s41467-020-16475-3 google scholar
  • Baar, M. P., Brandt, R. M. C., Putavet, D. A., Klein, J. D. D., Derks, K. W. J., Bourgeois, B. R. M., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D. A., van der Pluijm, I., Essers, J., van Cappellen, W. A., van IJcken, W. F., Houtsmuller, A. B., Pothof, J., de Bruin, R. W. F., Madl, T., Hoeijmakers, J. H. J., Campisi, J., & de Keizer, P. L. J. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147. https://doi.org/10. 1016/j.cell.2017.02.031 google scholar
  • Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., Saltness, R., Jeganathan, K. B., Versoza, G. C., Pezeshki, A. M., Khazaie, K., Miller, J. D., & van Deursen, J. M. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189. https://doi.org/10.1038/nature 16932 google scholar
  • Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. https://doi.org/10.1038/nature10600 google scholar
  • Bao, E., Zhou, Y., He, S., Tang, J., He, Y., Zhu, M., Cheng, C., &Wang, Y. (2023). RING box protein-1 (RBX1), a key component of SCF E3 ligase, induced multiple myeloma cell drug-resistance though suppressing p27. Cancer Biology & Therapy, 24(1), 2231670. https://doi.org/10.1080/15384047.2023.2231670 google scholar
  • Beauséjour, C. M., Krtolica, A., Galimi, F., Narita, M., Lowe, S. W., Yaswen, P., & Campisi, J. (2003). Reversal of human cellular senescence: roles of the p53 and p16 pathways. The EMBO journal, 22, 4212 – 4222. https://doi.org/10.1093/emboj/ cdg417 google scholar
  • Blagosklonny, M. V. (2013). Hypoxia, MTOR and autophagy: converging on senescence or quiescence. Autophagy, 9(2), 260-262. https://doi.org/10.4161/auto.22783 google scholar
  • Blain, S. W., Scher, H. I., Cordon-Cardo, C., & Koff, A. (2003). p27 as a target for cancer therapeutics. Cancer Cell, 3(2), 111-115. https://doi.org/10.1016/S1535-6108(03) 00026-6 google scholar
  • Boisvert, F. M., Hendzel, M. J., & Bazett-Jones, D. P. (2000). Promyelocytic leukemia (PML) nuclear bodies are protein structures that do not accumulate RNA. The Journal of cell biology, 148(2), 283-292. https://doi.org/10.1083/jcb.148.2.283 google scholar
  • Bojko, A., Czarnecka-Herok, J., Charzynska, A., Dabrowski, M., & Sikora, E. (2019). Diver- sity of the senescence phenotype of cancer cells treated with chemothera- peutic agents. Cells, 8(12), 1501. https://doi.org/10.3390/cells8121501 google scholar
  • Borrero, L. J. H., & El-Deiry, W. S. (2021). Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1876(1), 188556. https://doi.org/10.1016/j.bbcan.2021.188556 google scholar
  • Brenner, E., Schörg, B. F., Ahmetlić, F., Wieder, T., Hilke, F. J., Simon, N., … Röcken, M. (2020). Cancer immune control needs senescence induction by interferon- dependent cell cycle regulator pathways in tumours. Nature Communications, 11(1), 1335. https://doi.org/10.1038/s41467-020-14987-6 google scholar
  • Bryant, C. S., Kumar, S., Chamala, S., Shah, J., Pal, J., Haider, M., Seward, S., Qazi, A. M., Morris, R., Semaan, A., Shammas, M. A., Steffes, C., Potti, R. B., Prasad, M., Weaver, D. W., & Batchu, R. B. (2010). Sulforaphane induces cell cycle arrest by protecting RB-E2F-1 complex in epithelial ovarian cancer cells. Molecular cancer, 9, 1-9. https://doi.org/10.1186/1476-4598-9-47 google scholar
  • Cao, N., Yu, Y., Zhu, H., Chen, M., Chen, P., Zhuo, M., Mao, Y., Li, L., Zhao, Q., Wu, M., & Ye, M. (2020b). SETDB1 promotes the progression of colorectal cancer via epigenetically silencing p21 expression. Cell Death & Disease, 11(5), 351. https:// doi.org/10.1038/s41419-020-2561-6 google scholar
  • Cao, X., Hou, J., An, Q., Assaraf, Y. G., & Wang, X. (2020a). Towards the overcoming of anticancer drug resistance mediated by p53 mutations. Drug Resistance Updates, 49, 100671. https://doi.org/10.1016/j.drup.2019.100671 google scholar
  • Castilho, R. M., Squarize, C. H., Chodosh, L. A., Williams, B. O., & Gutkind, J. S. (2009). mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell, 5(3), 279-289. https://doi.org/10.1016/j.stem.2009.06.017 google scholar
  • Cayo, A., Segovia, R., Venturini, W., Moore-Carrasco, R., Valenzuela, C., & Brown, N. (2021). mTOR activity and autophagy in senescent cells, a complex partner- ship. International Journal of Molecular Sciences, 22(15), 8149. https://doi.org/ 10.3390/ijms22158149 google scholar
  • Cazzalini, O., Scovassi, A. I., Savio, M., Stivala, L. A., & Prosperi, E. (2010). Multiple roles of the cell cycle inhibitor p21CDKN1A in the DNA damage response. Mutation Research/Reviews in Mutation Research, 704(1-3), 12-20. https://doi.org/10. 1016/j.mrrev.2010.01.009 google scholar
  • Cecchini, M. J., Ishak, C. A., Passos, D. T., Warner, A., Palma, D. A., Howlett, C. J., Driman, D. K., & Dick, F. A. (2015). Loss of the retinoblastoma tumor suppressor correlates with improved outcome in patients with lung adenocarcinoma treated with surgery and chemotherapy. Human Pathology, 46(12), 1922-1934. https://doi. org/10.1016/j.humpath.2015.08.010 google scholar
  • Chandra, T., Kirschner, K., Thuret, J.-Y., Pope, B. D., Ryba, T., Newman, S., Ahmed, K., Samarajiwa, S. A., Salama, R., Carroll, T., Stark, R., Janky, R., Narita, M., Xue, L., Chicas, A., Nũnez, S., Janknecht, R., Hayashi-Takanaka, Y., Wilson, M. D., … Narita, M. (2012). Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation. Molecular Cell, 47(2), 203-214. https://doi.org/10.1016/j.molcel.2012.06.010 google scholar
  • Chen, Y. Q., Cipriano, S. C., Sarkar, F. H., Ware, J. L., & Arenkiel, J. M. (1995). p53- independent induction of p21 (WAF1) pathway is preserved during tumor progression. International Journal of Oncology, 7(4), 889-893. https://doi.org/ 10.3892/ijo.7.4.889 google scholar
  • Cheung, T. H., & Rando, T. A. (2013). Molecular regulation of stem cell quiescence. Nature reviews Molecular Cell Biology, 14(6), 329-340. https://doi.org/10.1038/nrm 3591 google scholar
  • Chipuk, J. E., Kuwana, T., Bouchier-Hayes, L., Droin, N. M., Newmeyer, D. D., Schuler, M., & Green, D. R. (2004). Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science, 303(5660), 1010-1014. https://doi.org/10.1126/science.1092734 google scholar
  • Cho, S., & Hwang, E. S. (2012). Status of mTOR activity may phenotypically differentiate senescence and quiescence. Molecules and Cells, 33, 597-604. http://dx.doi. org/10.1007%2Fs10059-012-0042-1 google scholar
  • Chu, I. M., Hengst, L., & Slingerland, J. M. (2008). The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nature Reviews Cancer, 8(4), 253-267. https://doi.org/10.1038/nrc2347 google scholar
  • Cooks, T., Pateras, I. S., Tarcic, O., Solomon, H., Schetter, A. J., Wilder, S., Lozano, G., Pikarsky, E., Forshew, T., Rozenfeld, N., Harpaz, N., Itzkowitz, S., Harris, C. C., Rotter, V., Gorgoulis, V. G., & Oren, M. (2013). Mutant p53 prolongs NF-κB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell, 23(5), 634-646. https://doi.org/10.1016/j.ccr.2013. 03.022 google scholar
  • Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y. U., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P.-Y., & Campisi, J. (2008). Senescence-associated secretory pheno- types reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biology, 6(12), e301. https://doi.org/10.1371/journal. pbio.0060301 google scholar
  • Correia-Melo, C., Marques, F. D. M., Anderson, R., Hewitt, G., Hewitt, R., Cole, J., Carroll, B. M., Miwa, S., Birch, J., Merz, A., Rushton, M. D., Charles, M., Jurk, D., Tait, S. W. G., Czapiewski, R., Greaves, L., Nelson, G., Bohlooly-Y, M., Rodriguez-Cuenca, S.,… Passos, J. F. (2016). Mitochondria are required for pro‐ageing features of the senescent phenotype. The EMBO Journal, 35(7), 724-742. https://doi.org/10. 15252/embj.201592862 google scholar
  • D'adda Di Fagagna, F. (2008). Living on a break: cellular senescence as a DNA-damage response. Nature Reviews Cancer, 8(7), 512-522. https://doi.org/10.1038/nrc 2440 google scholar
  • De Blander, H., Morel, A. P., Senaratne, A. P., Ouzounova, M., & Puisieux, A. (2021). Cel- lular plasticity: a route to senescence exit and tumorigenesis. Cancers, 13(18), 4561. https://doi.org/10.3390/cancers13184561 google scholar
  • De Chiara, G., Marcocci, M. E., Torcia, M., Lucibello, M., Rosini, P., Bonini, P., Higashimoto, Y., Damonte, G., Armirotti, A., Amodei, S., Palamara, A. T., Russo, T., Garaci, E., & Cozzolino, F. (2006). Bcl-2 Phosphorylation by p38 MAPK: identification of target sites and biologic consequences. Journal of Biological Chemistry, 281(30), 21353-21361. https://doi.org/10.1074/jbc.M511052200″, google scholar
  • de Keizer, P. L. J., Packer, L. M., Szypowska, A. A., Riedl-Polderman, P. E., van den Broek, N. J. F., de Bruin, A., Dansen, T. B., Marais, R., Brenkman, A. B., & Burgering, B. M. T. (2010). Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence. Cancer Research, 70(21), 8526-8536. https://doi.org/10.1158/0008-5472.CAN-10-1563 google scholar
  • Delfarah, A., Hartel, N. G., Zheng, D., Yang, J., & Graham, N. A. (2021). Identification of a proteomic signature of senescence in primary human mammary epithelial cells. Journal of Proteome Research, 20(11), 5169-5179. https://doi.org/10.1021/ acs.jproteome.1c00659 google scholar
  • Delmas, V., Beermann, F., Martinozzi, S., Carreira, S., Ackermann, J., Kumasaka, M., Denat, L., Goodall, J., Luciani, F., Viros, A., Demirkan, N., Bastian, B. C., Goding, C. R., & Larue, L. (2007). β-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development. Genes & Development, 21(22), 2923-2935. https://doi.org/10.1101/ gad.450107 google scholar
  • Demidenko, Z. N., & Blagosklonny, M. V. (2008). Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle, 7(21), 3355-3361. https:// doi.org/10.4161/cc.7.21.6919 google scholar
  • Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., Schurra, C., Garre’, M., Nuciforo, P. G., Bensimon, A., Maestro, R., Pelicci, P. G., & d’Adda di Fagagna, F. (2006). Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature, 444(7119), 638-642. https://doi.org/ 10.1038/nature05327 google scholar
  • Dolan, D. W., Zupanic, A., Nelson, G., Hall, P., Miwa, S., Kirkwood, T. B., & Shanley, D. P. (2015). Integrated stochastic model of DNA damage repair by non-homologous end joining and p53/p21-mediated early senescence signalling. PLoS Computational Biology, 11(5), e1004246. https://doi.org/10.1371/journal.pcbi.1004246 google scholar
  • Donnini, S., Monti, M., Castagnini, C., Solito, R., Botta, M., Schenone, S., Giachetti, A., & Ziche, M. (2007). Pyrazolo–pyrimidine‐derived c‐Src inhibitor reduces angio- genesis and survival of squamous carcinoma cells by suppressing vascular endothelial growth factor production and signaling. International Journal of Cancer, 120(5), 995-1004. https://doi.org/10.1002/ijc.22410 google scholar
  • Duy, C., Li, M., Teater, M., Meydan, C., Garrett-Bakelman, F. E., Lee, T. C., Chin, C. R., Durmaz, C., Kawabata, K. C., Dhimolea, E., Mitsiades, C. S., Doehner, H., google scholar
  • D'Andrea, R. J., Becker, M. W., Paietta, E. M., Mason, C. E., Carroll, M., & Melnic, A. M. (2021). Chemotherapy induces senescence-like resilient cells capable of initiating AML recurrence. Cancer Discovery, 11(6), 1542-1561. https://doi.org/10. 1158/2159-8290.CD-20-1375 google scholar
  • Eggert, T., Wolter, K., Ji, J., Ma, C., Yevsa, T., Klotz, S., Medina-Echeverz, J., Longerich, T., Forgues, M., Reisinger, F., Heikenwalder, M., Wang, X. W., Zender, L., & Greten, T. F. (2016). Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell, 30(4), 533-547. https://doi.org/10.1016/j.ccell.2016.09.003 google scholar
  • El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B (1993). WAF1, a potential mediator of p53 tumor suppression. Cell, 75(4), 817-825. https://doi.org/10.1016/0092-8674 (93)90500-p google scholar
  • Evangelou, K., Belogiannis, K., Papaspyropoulos, A., Petty, R., & Gorgoulis, V. G. (2023). Escape from senescence: molecular basis and therapeutic ramifications. The Journal of Pathology, 260(5), 649-665. https://doi.org/10.1002/path.6164 google scholar
  • Faget, D. V., Ren, Q., & Stewart, S. A. (2019). Unmasking senescence: context-dependent effects of SASP in cancer. Nature Reviews Cancer, 19(8), 439-453. https://doi. org/10.1038/s41568-019-0156-2 google scholar
  • Fan, D. N. Y., & Schmitt, C. A. (2019). Genotoxic stress-induced senescence. In M. Demaria (Ed.), Cellular senescence (Methods in Molecular Biology, Vol. 1896, pp. 455–469). Humana Press. https://doi.org/10.1007/978-1-4939-8931-7_10 google scholar
  • Frazier, M. W., He, X., Wang, J., Gu, Z., Cleveland, J. L., & Zambetti, G. P. (1998). Activation of c-myc gene expression by tumor-derived p53 mutants requires a discrete C-terminal domain. Molecular and Cellular Biology, 18(7), 3735–3743. https:// doi.org/10.1128/MCB.18.7.3735 google scholar
  • Freund, A., Patil, C. K., & Campisi, J. (2011). p38MAPK is a novel DNA damage response‐independent regulator of the senescence‐associated secretory phe- notype. The EMBO Journal, 30(8), 1536-1548. https://doi.org/10.1038/emboj. 2011.69 google scholar
  • Furukawa, K., & Kondo, T. (1998). Identification of the lamina‐associated‐polypeptide‐ 2‐binding domain of B‐type lamin. European Journal of Biochemistry, 251(3), 729-733. https://doi.org/10.1046/j.1432-1327.1998.2510729.x google scholar
  • Gao, H., Zhou, F., Li, R., Yuan, J., & Ye, L. (2023). E2F1 inhibits cellular senescence and promotes oxaliplatin resistance in colorectal cancer. Annals of Translational Medicine, 11(4), 185. https://doi.org/10.21037/atm-22-4054 google scholar
  • Gao, X. L., Zhang, M., Tang, Y. L., & Liang, X. H. (2017). Cancer cell dormancy: mecha- nisms and implications of cancer recurrence and metastasis. OncoTargets and Therapy, 2017(10), 5219-5228.. https://doi.org/10.2147/ott.s140854 google scholar
  • García-Fernández, R. A., García-Palencia, P., Sánchez, M. Á., Gil-Gómez, G., Sánchez, B., Rollán, E., Martín-Caballero, J., & Flores, J. M. (2011). Combined loss of p21waf1/cip1 and p27kip1 enhances tumorigenesis in mice. Laboratory investigation, 91(11), 1634-1642. https://doi.org/10.1038/labinvest.2011.133 google scholar
  • Gartel, A. L., & Radhakrishnan, S. K. (2005). Lost in transcription: p21 repression, mechanisms, and consequences. Cancer Research, 65(10), 3980-3985. https:// doi.org/10.1158/0008-5472.CAN-04-3995 google scholar
  • Ghanem, A., Al-Karmalawy, A. A., Abd El Maksoud, A. I., Hanafy, S. M., Emara, H. A., Saleh, R. M., & Elshal, M. F. (2022). Rumex Vesicarius L. extract improves the efficacy of doxorubicin in triple-negative breast cancer through inhibiting Bcl2, mTOR, JNK1 and augmenting p21 expression. Informatics in Medicine Unlocked, 29, 100869. https://doi.org/10.1016/j.imu.2022.100869 google scholar
  • Ghosh, D., Nandi, S., & Bhattacharjee, S. (2018). Combination therapy to checkmate Glioblastoma: clinical challenges and advances. Clinical and Translational Medicine, 7(1), 33. https://doi.org/10.1186/s40169-018-0211-8 google scholar
  • Giacinti, C., & Giordano, A. (2006). RB and cell cycle progression. Oncogene, 25(38), 5220-5227. https://doi.org/10.1038/sj.onc.1209615 google scholar
  • Glück, S., Guey, B., Gulen, M. F., Wolter, K., Kang, T.-W., Schmacke, N. A., Bridgeman, A., Rehwinkel, J., Zender, L., & Ablasser, A. (2017). Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nature Cell Biology, 19(9), 1061-1070. https://doi.org/10.1038/ncb3586 google scholar
  • Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., Gil, J., Hara, E., Krizhanovsky, V., Jurk, D., Maier, A. B., Narita, M., Niedernhofer, L., Passos, J. F., Robbins, P. D.,… Demaria, M. (2019). Cellular senescence: defining a path forward. Cell, 179(4), 813-827. https://doi.org/10.1016/j.cell.2019.10.005 google scholar
  • Gu, C., Peng, H., Lu, Y., Yang, H., Tian, Z., Yin, G., Zhang, W., Lu, S., Zhang, Y., & Yang, Y. (2017). BTK suppresses myeloma cellular senescence through activat- ing AKT/P27/Rb signaling. Oncotarget, 8(34), 56858. https://doi.org/10.18632/ oncotarget.18096 google scholar
  • Gu, Y., Xu, T., Fang, Y., Shao, J., Hu, T., Wu, X., Shen, H., Xu, Y., Zhang, J., Song, Y., Xia, Y., Shu, Y., & Ma, P. (2024). CBX4 counteracts cellular senescence to desensitize gastric cancer cells to chemotherapy by inducing YAP1 SUMOylation. Drug Resistance Updates, 77, 101136. https://doi.org/10.1016/j.drup.2024.101136 google scholar
  • Guan, D., & Kao, H. Y. (2015). The function, regulation and therapeutic implications of the tumor suppressor protein, PML. Cell & Bioscience, 5, 1-14. https://doi.org/ 10.1186/s13578-015-0051-9 google scholar
  • Gubern, A., Joaquin, M., Marquès, M., Maseres, P., Garcia-Garcia, J., Amat, R., González- Nuñez, D., Oliva, B., Real, F. X., de Nadal, E., & Posas, F. (2016). The N-terminal phosphorylation of RB by p38 bypasses its inactivation by CDKs and prevents proliferation in cancer cells. Molecular Cell, 64(1), 25-36. https://doi.org/10. 1016/j.molcel.2016.08.015 google scholar
  • Guo, Q., Lan, F., Yan, X., Xiao, Z., Wu, Y., & Zhang, Q. (2018). Hypoxia exposure induced cisplatin resistance partially via activating p53 and hypoxia inducible factor‑1α in non‑small cell lung cancer A549 cells. Oncology Letters, 16(1), 801-808. https://doi.org/10.3892/ol.2018.8767 google scholar
  • Han, J., Wu, J., & Silke, J. (2020). An overview of mammalian p38 mitogen- activated protein kinases, central regulators of cell stress and receptor signal- ing. F1000Research, 9, 653. https://doi.org/10.12688/f1000research.22092.1 google scholar
  • Haq, R., Brenton, J. D., Takahashi, M., Finan, D., Rottapel, R., & Zanke, B. (2002). Constitu- tive p38HOG mitogen-activated protein kinase activation induces permanent cell cycle arrest and senescence. Cancer Research, 62(17), 5076-5082. Retrieved from https://pubmed.ncbi.nlm.nih.gov/12208764/ google scholar
  • Hernandez-Segura, A., Nehme, J., & Demaria, M. (2018). Hallmarks of cellular senes- cence. Trends in Cell Biology, 28(6), 436-453. https://doi.org/10.1016/j.tcb.2018. 02.001 google scholar
  • Herranz, N., & Gil, J. (2018). Mechanisms and functions of cellular senescence. The Journal of Clinical Investigation, 128(4), 1238-1246. https://doi.org/10.1172/JCI 95148 google scholar
  • Herranz, N., Gallage, S., Mellone, M., Wuestefeld, T., Klotz, S., Hanley, C. J., Raguz, S., Acosta, J. C., Innes, A. J., Banito, A., Georgilis, A., Montoya, A., Wolter, K., Dharma- lingam, G., Faull, P., Carroll, T., Martínez-Barbera, J. P., Cutillas, P., Reisinger, F., … Gil, J. (2015). mTOR regulates MAPKAPK2 translation to control the senescence- associated secretory phenotype. Nature Cell Biology, 17(9), 1205-1217. https:// doi.org/10.1038/ncb3225 google scholar
  • Hilgendorf, K. I., Leshchiner, E. S., Nedelcu, S., Maynard, M. A., Calo, E., Ianari, A., Walen- sky, L. D., & Lees, J. A. (2013). The retinoblastoma protein induces apoptosis directly at the mitochondria. Genes & Development, 27(9), 1003-1015. https:// doi.org/10.1101/gad.211326.112 google scholar
  • Hoare, M., Ito, Y., Kang, T.-W., Weekes, M. P., Matheson, N. J., Patten, D. A., Shetty, S., Parry, A. J., Menon, S., Salama, R., Antrobus, R., Tomimatsu, K., Howat, W., Lehner, P. J., Zender, L., & Narita, M. (2016). NOTCH1 mediates a switch between two distinct secretomes during senescence. Nature Cell Biology, 18(9), 979-992. https://doi. org/10.1038/ncb3397 google scholar
  • Hoque, M. M., Iida, Y., Kotani, H., & Harada, M. (2024). Senolysis of gemcitabine‐ induced senescent human pancreatic cancer cells. Cancer Reports, 7(4), e2075. https://doi.org/10.1002/cnr2.2075 google scholar
  • Hsu, C. H., Altschuler, S. J., & Wu, L. F. (2019). Patterns of early p21 dynamics determine proliferation-senescence cell fate after chemotherapy. Cell, 178(2), 361-373. https://doi.org/10.1016/j.cell.2019.05.041 google scholar
  • Huggins, C. J., Malik, R., Lee, S., Salotti, J., Thomas, S., Martin, N., Quiñones, O. A., Alvord, W. G., Olanich, M. E., Keller, J. R., & Johnson, P. F. (2013). C/EBPγ suppresses senescence and inflammatory gene expression by heterodimerizing with C/ EBPβ. Molecular and Cellular Biology. https://doi.org/10.1128/MCB.01674-12 google scholar
  • Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W., & Raulet, D. H. (2013). p53- dependent chemokine production by senescent tumor cells supports NKG2D- dependent tumor elimination by natural killer cells. Journal of Experimental Medicine, 210(10), 2057-2069. https://doi.org/10.1084/jem.20130783 google scholar
  • Imai, Y., Takahashi, A., Hanyu, A., Hori, S., Sato, S., Naka, K., Hirao, A., Ohtani, N., & Hara, E. (2014). Crosstalk between the Rb pathway and AKT signaling forms a quiescence-senescence switch. Cell Reports, 7(1), 194-207. https://doi.org/10. 1016/j.celrep.2014.03.006 google scholar
  • Iwasa, H., Han, J., & Ishikawa, F. (2003). Mitogen‐activated protein kinase p38 defines the common senescence‐signalling pathway. Genes to Cells, 8(2), 131-144. https://doi.org/10.1046/j.1365-2443.2003.00620.x google scholar
  • Jin, S., Tong, T., Fan, W., Fan, F., Antinore, M. J., Zhu, X., Mazzacurati, L., Li, X., Petrik, K. L., Rajasekaran, B., Wu, M., & Zhan, Q. (2002). GADD45-induced cell cycle G2- M arrest associates with altered subcellular distribution of cyclin B1 and is independent of p38 kinase activity. Oncogene, 21(57), 8696-8704. https://doi. org/10.1038/sj.onc.1206034 google scholar
  • Jin, X., Ding, D., Yan, Y., Li, H., Wang, B., Ma, L., Ye, Z., Ma, T., Wu, Q., Rodrigues, D. N., Kohli, M., Jimenez, R., Wang, L., Goodrich, D. W., de Bono, J., Dong, H., Wu, H., Zhu, R., & Huang, H. (2019). Phosphorylated RB promotes cancer immunity by inhibiting NF-κB activation and PD-L1 expression. Molecular Cell, 73(1), 22-35. https://doi.org/10.1016/j.molcel.2018.10.034 google scholar
  • Joaquin, M., de Nadal, E., & Posas, F. (2017). An RB insensitive to CDK regulation. Molecular & Cellular Oncology, 4(1), e1268242. https://doi.org/10.1080/23723556. 2016.1268242 google scholar
  • Johmura, Y., Yamanaka, T., Omori, S., Wang, T., Sugiura, Y., Matsumoto, M., Suzuki, N., Kumamoto, S., Yamaguchi, K., Hatakeyama, S., Takami, T., Yamaguchi, R., Shimizu, E., Ikeda, K., Okahashi, N., Mikawa, R., Suematsu, M., Arita, M., Sugimoto, M., … Nakanishi, M. (2021). Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science, 371(6526), 265-270. https://doi.org/ 10.1126/science.abb5916 google scholar
  • Jung, S. H., Hwang, H. J., Kang, D., Park, H. A., Lee, H. C., Jeong, D., Lee, K., Park, H. J., Ko, Y.-G., & Lee, J.-S. (2019). mTOR kinase leads to PTEN-loss-induced cellular senescence by phosphorylating p53. Oncogene, 38(10), 1639-1650. https://doi. org/10.1038/s41388-018-0521-8 google scholar
  • Katoh, M., & Katoh, M. (2022). WNT signaling and cancer stemness. Essays in Biochemistry, 66(4), 319-331. https://doi.org/10.1042/EBC20220016 google scholar
  • Kim, E., Giese, A., & Deppert, W. (2009). Wild-type p53 in cancer cells: when a guardian turns into a blackguard. Biochemical Pharmacology, 77(1), 11-20. https://doi. org/10.1016/j.bcp.2008.08.030 google scholar
  • Kim, K. M., Noh, J. H., Bodogai, M., Martindale, J. L., Yang, X., Indig, F. E., Basu, S. K., Ohnuma, K., Morimoto, C., Johnson, P. F., Biragyn, A., Abdelmohsen, K., & Gorospe, M. (2017). Identification of senescent cell surface targetable protein DPP4. Genes & Development, 31(15), 1529-1534. https://doi.org/10.1101/gad. 302570.117 google scholar
  • Kitaura, H., Shinshi, M., Uchikoshi, Y., Ono, T., Tsurimoto, T., Yoshikawa, H., Iguchi- Ariga, S. M. M., & Ariga, H.. (2000). Reciprocal regulation via protein-protein interaction between c-Myc and p21 cip1/waf1/sdi1 in DNA replication and transcription. Journal of Biological Chemistry, 275(14), 10477-10483. https://doi. org/10.1074/jbc.275.14.10477 google scholar
  • Kohli, J., Wang, B., Brandenburg, S. M., Basisty, N., Evangelou, K., Varela-Eirin, M., Campisi, J., Schilling, B., Gorgoulis, V., & Demaria, M. (2021). Algorithmic assess- ment of cellular senescence in experimental and clinical specimens. Nature Protocols, 16(5), 2471-2498. https://doi.org/10.1038/s41596-021-00505-5 google scholar
  • Kopp, H. G., Hooper, A. T., Shmelkov, S. V., & Rafii, S. (2007). ß-Galactosidase staining on bone marrow. The osteoclast pitfall. Histology and Histopathology. https:// doi.org/10.14670/hh-22.971 google scholar
  • Kreis, N. N., Louwen, F., & Yuan, J. (2019). The multifaceted p21 (Cip1/Waf1/CDKN1A) in cell differentiation, migration and cancer therapy. Cancers, 11(9), 1220. https:// doi.org/10.3390/cancers11091220 google scholar
  • Kuilman, T., Michaloglou, C., Vredeveld, L. C. W., Douma, S., van Doorn, R., Desmet, C. J., Aarden, L. A., Mooi, W. J., & Peeper, D. S. (2008). Oncogene-induced senes- cence relayed by an interleukin-dependent inflammatory network. Cell, 133(6), 1019-1031. https://doi.org/10.1016/j.cell.2008.03.039 google scholar
  • Kumar, B., Koul, S., Petersen, J., Khandrika, L., Hwa, J. S., Meacham, R. B., Wilson, S., & Koul, H. K. (2010). p38 mitogen-activated protein kinase–driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity. Cancer Research, 70(2), 832-841. https://doi.org/10.1158/0008-5472. CAN-09-2918 google scholar
  • Kwak, A.-W., Park, J. W., Lee, S.-O., Lee, J.-Y., Seo, J.-H., Yoon, G., Lee, M.-H., Choi, J.-S., & Shim, J.-H. (2022). Isolinderalactone sensitizes oxaliplatin-resistance colorec- tal cancer cells through JNK/p38 MAPK signaling pathways. Phytomedicine, 105, 154383. https://doi.org/10.1016/j.phymed.2022.154383 google scholar
  • Kwong, J., Hong, L., Liao, R., Deng, Q., Han, J., & Sun, P. (2009). p38α and p38γ mediate oncogenic ras-induced senescence through differential mechanisms. Journal of Biological Chemistry, 284(17), 11237-11246. https://doi.org/10.1074/jbc.M 808327200 google scholar
  • Laberge, R.-M., Sun, Y., Orjalo, A. V., Patil, C. K., Freund, A., Zhou, L., Curran, S. C., Davalos, A. R., Wilson-Edell, K. A., Liu, S., Limbad, C., Demaria, M., Li, P., Hubbard, G. B., Ikeno, Y., Javors, M., Desprez, P.-Y., Benz, C. C., Kapahi, P., Nelson, P. S., & Campisi, J. (2015). MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nature Cell Biology, 17(8), 1049-1061. https://doi.org/10.1038/ncb3195 google scholar
  • Lafarga, V., Cuadrado, A., Lopez de Silanes, I., Bengoechea, R., Fernandez-Capetillo, O., & Nebreda, A. R. (2009). p38 Mitogen-activated protein kinase-and HuR- dependent stabilization of p21Cip1 mRNA mediates the G1/S checkpoint. Molecular and Cellular Biology, 29(16), 4341-4351. https://doi.org/10.1128/MCB. 00210-09 google scholar
  • Le, O. N. L., Rodier, F., Fontaine, F., Coppe, J.-P., Campisi, J., DeGregori, J., Laverdière, C., Kokta, V., Haddad, E., & Beauséjour, C. M. (2010). Ionizing radiation‐induced long‐term expression of senescence markers in mice is independent of p53 and immune status. Aging Cell, 9(3), 398-409. https://doi.org/10.1111/j.1474- 9726.2010.00567.x google scholar
  • Lee, B. Y., Han, J. A., Im, J. S., Morrone, A., Johung, K., Goodwin, E. C., Kleijer, W. J., DiMaio, D., & Hwang, E. S. (2006). Senescence‐associated β‐galactosidase is lysosomal β‐galactosidase. Aging cell, 5(2), 187-195. https://doi.org/10.1111/j. 1474-9726.2006.00199.x google scholar
  • Lee, H. L., Lin, C. S., Kao, S. H., & Chou, M. C. (2017). Gallic acid induces G1 phase arrest and apoptosis of triple-negative breast cancer cell MDA-MB-231 via p38 mitogen-activated protein kinase/p21/p27 axis. Anti-cancer drugs, 28(10), 1150-1156. https://doi.org/10.1097/cad.0000000000000565 google scholar
  • Lee, S., & Schmitt, C. A. (2019). The dynamic nature of senescence in cancer. Nature cell biology, 21(1), 94-101. https://doi.org/10.1038/s41556-018-0249-2 google scholar
  • Leelahavanichkul, K., Amornphimoltham, P., Molinolo, A. A., Basile, J. R., Koon- tongkaew, S., & Gutkind, J. S. (2014). A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogene- sis. Molecular Oncology, 8(1), 105-118. https://doi.org/10.1016/j.molonc.2013.10. 003 google scholar
  • Leontieva, O. V., & Blagosklonny, M. V. (2013). CDK4/6-inhibiting drug substitutes for p21 and p16 in senescence: duration of cell cycle arrest and MTOR activity determine geroconversion. Cell Cycle, 12(18), 3063-3069. https://doi.org/10. 4161/cc.26130 google scholar
  • Leontieva, O. V., Gudkov, A. V., & Blagosklonny, M. V. (2010). Weak p53 permits senes- cence during cell cycle arrest. Cell Cycle, 9(21), 4323-4327. https://doi.org/10. 4161/cc.9.21.13584 google scholar
  • Lessard, F., Igelmann, S., Trahan, C., Huot, G., Saint-Germain, E., Mignacca, L., Del Toro, N., Lopes-Paciencia, S., Le Calvé, B., Montero, M., Deschênes-Simard, X., Bury, M., Moiseeva, O., Rowell, M.-C., Zorca, C. E., Zenklusen, D., Brakier-Gingras, L., Bourdeau, V., Oeffinger, M., & Ferbeyre, G. (2018). Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway. Nature Cell Biology, 20(7), 789-799. https://doi.org/10.1038/s41556- 018-0127-y google scholar
  • Li, M., Yang, J., Liu, K., Yang, J., Zhan, X., Wang, L., Shen, X., Chen, J., & Mao, Z. (2020). p16 promotes proliferation in cervical carcinoma cells through CDK6-HuR-IL1A axis. Journal of Cancer, 11(6), 1457-1467. https://doi.org/10.7150/jca.35479 google scholar
  • Li, P., Pu, S., Lin, C., He, L., Zhao, H., Yang, C., Guo, Z., Xu, S., & Zhou, Z. (2022). Curcumin selectively induces colon cancer cell apoptosis and S cell cycle arrest by regulates Rb/E2F/p53 pathway. Journal of Molecular Structure, 1263, 133180. https://doi.org/10.1016/j.molstruc.2022.133180 google scholar
  • Li, Y., Nichols, M. A., Shay, J. W., & Xiong, Y. (1994). Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma suscep- tibility gene product pRb. Cancer Research, 54(23), 6078-6082. Retrieved from https://pubmed.ncbi.nlm.nih.gov/7954450/ google scholar
  • Liang, Y., Liang, N., Ma, Y., Tang, S., Ye, S., & Xiao, F. (2021). Role of Clusterin/NF-κB in the secretion of senescence-associated secretory phenotype in Cr (VI)-induced premature senescent L-02 hepatocytes. Ecotoxicology and Environmental Safety, 219, 112343. https://doi.org/10.1016/j.ecoenv.2021.112343 google scholar
  • Lin, C., Li, H., Liu, J., Hu, Q., Zhang, S., Zhang, N., Liu, L., Dai, Y., Cao, D., Li, X., Huang, B., Lu, J., & Zhang, Y. (2020). Arginine hypomethylation-mediated proteasomal degradation of histone H4—an early biomarker of cellular senescence. Cell Death & Differentiation, 27(9), 2697-2709. https://doi.org/10.1038/s41418-020- 0562-8 google scholar
  • Lisek, K., Campaner, E., Ciani, Y., Walerych, D., & Del Sal, G. (2018). Mutant p53 tunes the NRF2-dependent antioxidant response to support survival of cancer cells. Oncotarget, 9(29), 20508. https://doi.org/10.18632/oncotarget.24974 google scholar
  • Lisek, K., Walerych, D., & Del Sal, G. (2017). Mutant p53–Nrf2 axis regulates the proteasome machinery in cancer. Molecular & Cellular Oncology, 4(1), e1217967. https://doi.org/10.1080/23723556.2016.1217967 google scholar
  • Liu, G. Y., & Sabatini, D. M. (2020). mTOR at the nexus of nutrition, growth, ageing and disease. Nature reviews Molecular Cell Biology, 21(4), 183-203. https://doi.org/ 10.1038/s41580-019-0199-y google scholar
  • Liu, M., Casimiro, M. C., Wang, C., Shirley, L. A., Jiao, X., Katiyar, S., Ju, X., Li, Z., Yu, Z., Zhou, J., Johnson, M., Fortina, P., Hyslop, T., Windle, J. J., & Pestell, R. G. (2009). p21CIP1 attenuates Ras-and c-Myc-dependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo. Proceedings of the National Academy of Sciences, 106(45), 19035-19039. https://doi.org/10. 1073/pnas.0910009106 google scholar
  • Liu, Z., Lin, H., Gan, Y., Cui, C., Zhang, B., Gu, L., Zhou, J., Zhu, G., & Deng, D. (2019). P16 methylation leads to paclitaxel resistance of advanced non-small cell lung cancer. Journal of Cancer, 10(7), 1726-1733. https://doi.org/10.7150/jca.26482 google scholar
  • Liu, Z., Sun, M., Lu, K., Liu, J., Zhang, M., Wu, W., De, W., Wang, Z., & Wang, R. (2013). The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21WAF1/CIP1 expression. PloS One, 8(10), e77293. https://doi.org/10.1371/journal.pone.0077293 google scholar
  • Loewith, R., Jacinto, E., Wullschleger, S., Lorberg, A., Crespo, J. L., Bonenfant, D., Oppliger, W., Jenoe, P., & Hall, M. N. (2002). Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Molecular Cell, 10(3), 457-468. https://doi.org/10.1016/S1097-2765(02)00636-6 google scholar
  • Lord, C. J., & Ashworth, A. (2012). The DNA damage response and cancer therapy. Nature, 481(7381), 287-294. https://doi.org/10.1038/nature10760 google scholar
  • Lossaint, G., Horvat, A., Gire, V., Bačević, K., Mrouj, K., Charrier-Savournin, F., Georget, V., Fisher, D., & Dulić, V. (2022). Reciprocal regulation of p21 and Chk1 controls the cyclin D1-RB pathway to mediate senescence onset after G2 arrest. Journal of cell Science, 135(8), jcs259114. https://doi.org/10.1242/jcs.259114 google scholar
  • Ma, Z., Cai, Y., & Tian, C. (2023). ZWINT promotes the proliferation, migration, and invasion of cervical cancer cells by regulating the p53/p21 signaling pathway. Journal of Physiology Investigation, 66(5), 372-378. https://doi.org/10. 4103/cjop.cjop-d-23-00001 google scholar
  • Maddison, L. A., Sutherland, B. W., Barrios, R. J., & Greenberg, N. M. (2004). Conditional deletion of Rb causes early stage prostate cancer. Cancer Research, 64(17), 6018-6025. https://doi.org/10.1158/0008-5472.CAN-03-2509 google scholar
  • Maiuthed, A., Ninsontia, C., Erlenbach-Wuensch, K., Ndreshkjana, B., Muenzner, J. K., Caliskan, A., Ahmed, H. P., Chaotham, C., Hartmann, A., Vial Roehe, A., Mahadevan, V., Chanvorachote, P., & Schneider-Stock, R. (2018). Cytoplasmic p21 mediates 5-fluorouracil resistance by inhibiting pro-apoptotic Chk2. Cancers, 10(10), 373. https://doi.org/10.3390/cancers10100373 google scholar
  • Mak, V. C., Li, X., Rao, L., Zhou, Y., Tsao, S. W., & Cheung, L. W. (2021). p85β alters response to EGFR inhibitor in ovarian cancer through p38 MAPK-mediated regulation of DNA repair. Neoplasia, 23(7), 718-730. https://doi.org/10.1016/j.neo.2021.05.009 google scholar
  • Maki, C. G. (2010). Decision-making by p53 and mTOR. Aging (Albany NY), 2(6), 324-326. https://doi.org/10.18632/aging.100166 google scholar
  • Mandigo, A. C., Yuan, W., Xu, K., Gallagher, P., Pang, A., Guan, Y. F., Shafi, A. A., Thangavel, C., Sheehan, B., Bogdan, D., Paschalis, A., McCann, J. J., Laufer, T. S., Gordon, N., Vasilevskaya, I. A., Dylgjeri, E., Chand, S. N., Schiewer, M. J., Domingo-Domenech, J., … & Knudsen, K. E. (2021). RB/E2F1 as a master regulator of cancer cell metabolism in advanced disease. Cancer Discovery, 11(9), 2334-2353. https:// doi.org/10.1158/2159-8290.CD-20-1114 google scholar
  • Mansilla, S. F., De La Vega, M. B., Calzetta, N. L., Siri, S. O., & Gottifredi, V. (2020). CDK-independent and PCNA-dependent functions of p21 in DNA repli- cation. Genes, 11(6), 593. https://doi.org/10.3390/genes11060593 google scholar
  • Marusyk, A., Tabassum, D. P., Altrock, P. M., Almendro, V., Michor, F., & Polyak, K. (2014). Non-cell-autonomous driving of tumour growth supports sub-clonal hetero- geneity. Nature, 514(7520), 54-58. https://doi.org/10.1038/nature13556 google scholar
  • Maskey, R. S., Wang, F., Lehman, E., Wang, Y., Emmanuel, N., Zhong, W., Jin, G., Abraham, R. T., Arndt, K. T., Myers, J. S., & Mazurek, A. (2021). Sustained mTORC1 activity during palbociclib-induced growth arrest triggers senescence in ER+ breast cancer cells. Cell Cycle, 20(1), 65-80. https://doi.org/10.1080/15384101. 2020.1859195 google scholar
  • McNair, C., Xu, K., Mandigo, A. C., Benelli, M., Leiby, B., Rodrigues, D., Lindberg, J., Gron- berg, H., Crespo, M., De Laere, B., Dirix, L., Visakorpi, T., Li, F., Feng, F. Y., de Bono, J., Demichelis, F., Rubin, M. A., Brown, M., & Knudsen, K. E. (2018). Differential impact of RB status on E2F1 reprogramming in human cancer. The Journal of Clinical Investigation, 128(1), 341-358. https://doi.org/10.1172/JCI93566 google scholar
  • Mihara, M., Erster, S., Zaika, A., Petrenko, O., Chittenden, T., Pancoska, P., & Moll, U. M. (2003). p53 has a direct apoptogenic role at the mitochondria. Molecular Cell, 11(3), 577-590. https://doi.org/10.1016/S1097-2765(03)00050-9 google scholar
  • Milanovic, M., Yu, Y., & Schmitt, C. A. (2018). The senescence–stemness alliance–a can- cer-hijacked regeneration principle. Trends in Cell Biology, 28(12), 1049-1061. https://doi.org/10.1016/j.tcb.2018.09.001 google scholar
  • Moiseeva, O., Deschênes-Simard, X., St-Germain, E., Igelmann, S., Huot, G., Cadar, A. E., Bourdeau, V., Pollak, M. N., & Ferbeyre, G. (2013). Metformin inhibits the senescence‐associated secretory phenotype by interfering with IKK/NF‐κ B activation. Aging Cell, 12(3), 489-498. https://doi.org/10.1111/acel.12075 google scholar
  • Momtaz, S., Baeeri, M., Rahimifard, M., Haghi‐Aminjan, H., Hassani, S., & Abdollahi, M. (2019). Manipulation of molecular pathways and senescence hallmarks by natural compounds in fibroblast cells. Journal of Cellular Biochemistry, 120(4), 6209-6222. https://doi.org/10.1002/jcb.27909 google scholar
  • Mondal, P., Mohapatra, S., Bhunia, D., Gharai, P. K., Mukherjee, N., Gupta, V., Ghosh, S., & Ghosh, S. (2022). Designed hybrid anticancer nuclear-localized peptide inhibits aggressive cancer cell proliferation. RSC Medicinal Chemistry, 13(2), 196-201. https://doi.org/10.1039/D1MD00324K google scholar
  • Morgunova, G. V., Kolesnikov, A. V., Klebanov, A. A., & Khokhlov, A. N. (2015). Senes- cence-associated β-galactosidase—A biomarker of aging, DNA damage, or cell proliferation restriction?. Moscow University Biological Sciences Bulletin, 70, 165-167. https://doi.org/10.3103/S0096392515040082 google scholar
  • Moss, S. C., Lightell, D. J., Marx, S. O., Marks, A. R., & Woods, T. C. (2010). Rapamycin reg- ulates endothelial cell migration through regulation of the cyclin-dependent kinase inhibitor p27Kip1. Journal of Biological Chemistry, 285(16), 11991-11997. https://doi.org/10.1074/jbc.M109.066621 google scholar
  • Mossmann, D., Park, S., & Hall, M. N. (2018). mTOR signalling and cellular metabolism are mutual determinants in cancer. Nature Reviews Cancer, 18(12), 744-757. https://doi.org/10.1038/s41568-018-0074-8 google scholar
  • Mosteiro, L., Pantoja, C., de Martino, A., & Serrano, M. (2018). Senescence promotes in vivo reprogramming through p16 INK 4a and IL‐6. Aging Cell, 17(2), e12711. https://doi.org/10.1111/acel.12711 google scholar
  • Mrouj, K., Andrés-Sánchez, N., Dubra, G., Singh, P., Sobecki, M., Chahar, D., Al Ghoul, E., Aznar, A. B., Prieto, S., Pirot, N., Bernex, F., Bordignon, B., Hassen-Khodja, C., Villalba, M., Krasinska, L., & Fisher, D. (2021). Ki-67 regulates global gene expression and promotes sequential stages of carcinogenesis. Proceedings of the National Academy of Sciences, 118(10), e2026507118. https://doi.org/10. 1073/pnas.2026507118 google scholar
  • Munro, S., Carr, S. M., & La Thangue, N. B. (2012). Diversity within the pRb pathway: is there a code of conduct?. Oncogene, 31(40), 4343-4352. https://doi.org/10. 1038/onc.2011.603 google scholar
  • Nagahara, H., Vocero-Akbani, A. M., Snyder, E. L., Ho, A., Latham, D. G., Lissy, N. A., Becker-Hapak, M., Ezhevsky, S. A., & Dowdy, S. F. (1998). Transduction of full- length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration. Nature Medicine, 4(12), 1449-1452. https://doi.org/10.1038/4042 google scholar
  • Narita, M., Nuñez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., & Lowe, S. W. (2003). Rb-mediated heterochromatin formation and google scholar
  • silencing of E2F target genes during cellular senescence. Cell, 113(6), 703-716. https://doi.org/10.1016/S0092-8674(03)00401-X google scholar
  • Niederst, M. J., Sequist, L. V., Poirier, J. T., Mermel, C. H., Lockerman, E. L., Garcia, A. R., Katayama, R., Costa, C., Ross, K. N., Moran, T., Howe, E., Fulton, L. E., Mulvey, H. E., Bernardo, L. A., Mohamoud, F., Miyoshi, N., VanderLaan, P. A., Costa, D. B., Jänne, P. A., & Engelman, J. A. (2015). RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nature Communications, 6(1), 6377. https://doi.org/10.1038/ncomms7377 google scholar
  • Nilsson, M. B., Langley, R. R., & Fidler, I. J. (2005). Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Research, 65(23), 10794-10800. https://doi.org/10.1158/0008-5472.CAN-05-0623 google scholar
  • Niu, L. L., Cheng, C. L., Li, M. Y., Yang, S. L., Hu, B. G., Chong, C. C., Chan, S. L., Ren, J., Chen, G. G., & Lai, P. B. S. (2018). ID1-induced p16/IL6 axis activation contributes to the resistant of hepatocellular carcinoma cells to sorafenib. Cell Death & Disease, 9(9), 852. https://doi.org/10.1038/s41419-018-0926-x google scholar
  • Nowosad, A., Jeannot, P., Callot, C., Creff, J., Perchey, R. T., Joffre, C., Codogno, P., Manenti, S., & Besson, A. (2020). p27 controls Ragulator and mTOR activity in amino acid- deprived cells to regulate the autophagy–lysosomal pathway and coordinate cell cycle and cell growth. Nature Cell Biology, 22(9), 1076-1090. https://doi. org/10.1038/s41556-020-0554-4 google scholar
  • Ohtani, N. (2022). The roles and mechanisms of senescence-associated secretory phenotype (SASP): can it be controlled by senolysis?. Inflammation and Regeneration, 42(1), 11. https://doi.org/10.1186/s41232-022-00197-8 google scholar
  • Okuma, A., Hanyu, A., Watanabe, S., & Hara, E. (2017). p16Ink4a and p21Cip1/ Waf1 promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis. Nature Communications, 8(1), 2050. https://doi.org/10.1038/ s41467-017-02281-x google scholar
  • Olszewska, A., Borkowska, A., Granica, M., Karolczak, J., Zglinicki, B., Kieda, C., & Was, H. (2022). Escape from cisplatin-induced senescence of hypoxic lung cancer cells can be overcome by hydroxychloroquine. Frontiers in Oncology, 11, 738385. https://doi.org/10.3389/fonc.2021.738385 google scholar
  • Pack, L. R., Daigh, L. H., & Meyer, T. (2019). Putting the brakes on the cell cycle: mecha- nisms of cellular growth arrest. Current Opinion in Cell Biology, 60, 106-113. https://doi.org/10.1016/j.ceb.2019.05.005 google scholar
  • Palafox, M., Monserrat, L., Bellet, M., Villacampa, G., Gonzalez-Perez, A., Oliveira, M., Brasó-Maristany, F., Ibrahimi, N., Kannan, S., Mina, L., Herrera-Abreu, M. T., Òdena, A., Sánchez-Guixé, M., Capelán, M., Azaro, A., Bruna, A., Rodríguez, O., Guzmán, M., Grueso, J., … & Serra, V. (2022). High p16 expression and heterozy- gous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer. Nature Communications, 13(1), 5258. https://doi.org/10.1038/s41467- 022-32828-6 google scholar
  • Pang, X., Gao, S., Liu, T., Xu, F. X., Fan, C., Zhang, J. F., & Jiang, H. (2024). Identification of STAT3 as a biomarker for cellular senescence in liver fibrosis: A bioinformatics and experimental validation study. Genomics, 116(2), 110800. https://doi.org/ 10.1016/j.ygeno.2024.110800 google scholar
  • Park, S. Y., & Nam, J. S. (2020). The force awakens: metastatic dormant cancer cells. Experimental & Molecular Medicine, 52(4), 569-581. https://doi.org/10. 1038/s12276-020-0423-z google scholar
  • Passos, J. F., Nelson, G., Wang, C., Richter, T., Simillion, C., Proctor, C. J., Miwa, S., Olijs- lagers, S., Hallinan, J., Wipat, A., Saretzki, G., Rudolph, K. L., Kirkwood, T. B. L., & von Zglinicki, T. (2010). Feedback between p21 and reactive oxygen production is necessary for cell senescence. Molecular Systems Biology, 6(1), 347. https:// doi.org/10.1038/msb.2010.5 google scholar
  • Piechota, M., Sunderland, P., Wysocka, A., Nalberczak, M., Sliwinska, M. A., Radwanska, K., & Sikora, E. (2016). Is senescence-associated β-galactosidase a marker of neuronal senescence?. Oncotarget, 7(49), 81099-81109. https://doi.org/10. 18632/oncotarget.12752 google scholar
  • Pietsch, E. C., Perchiniak, E., Canutescu, A. A., Wang, G., Dunbrack, R. L., & Murphy, M. E. (2008). Oligomerization of BAK by p53 utilizes conserved residues of the p53 DNA binding domain. Journal of Biological Chemistry, 283(30), 21294-21304. https://doi.org/10.1074/jbc.M710539200 google scholar
  • Puri, P. L., Wu, Z., Zhang, P., Wood, L. D., Bhakta, K. S., Han, J., Feramisco, J. R., Karin, M., & Wang, J. Y. J. (2000). Induction of terminal differentiation by constitutive activation of p38 MAP kinase in human rhabdomyosarcoma cells. Genes & development, 14(5), 574-584. Retrieved from https://pubmed.ncbi.nlm.nih.gov/ 10716945/ google scholar
  • Rajendran, P., Alzahrani, A. M., Hanieh, H. N., Kumar, S. A., Ben Ammar, R., Rengarajan, T., & Alhoot, M. A. (2019). Autophagy and senescence: A new insight in selected human diseases. Journal of Cellular Physiology, 234(12), 21485-21492. https:// doi.org/10.1002/jcp.28895 google scholar
  • Rayess, H., Wang, M. B., & Srivatsan, E. S. (2012). Cellular senescence and tumor suppressor gene p16. International Journal of Cancer, 130(8), 1715-1725. https:// doi.org/10.1002/ijc.27316 google scholar
  • Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., Sansom, O. J., Zender, L., & Keyes, W. M. (2017). The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & Development, 31(2), 172-183. https://doi.org/10.1101/gad.290635.116 google scholar
  • Rodier, F., Coppé, J.-P., Patil, C. K., Hoeijmakers, W. A. M., Muñoz, D. P., Raza, S. R., Freund, A., Campeau, E., Davalos, A. R., & Campisi, J. (2009). Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine se- cretion. Nature Cell Biology, 11(8), 973-979. https://doi.org/10.1038/ncb1909 google scholar
  • Rodier, F., Muñoz, D. P., Teachenor, R., Chu, V., Le, O., Bhaumik, D., Coppé, J.-P., Campeau, E., Beauséjour, C. M., Kim, S.-H., Davalos, A. R., & Campisi, J. (2011). DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. Journal of Cell Science, 124(1), 68-81. https://doi.org/10.1242/jcs.071340 google scholar
  • Ruefli, A. A., & Johnstone, R. W. (2003). A role for P-glycoprotein in regulating cell growth and survival. Clinical and Applied Immunology Reviews, 4(1), 31-47. https://doi.org/10.1016/S1529-1049(03)00005-9 google scholar
  • Ruhland, M. K., Loza, A. J., Capietto, A.-H., Luo, X., Knolhoff, B. L., Flanagan, K. C., Belt, B. A., Alspach, E., Leahy, K., Luo, J., Schaffer, A., Edwards, J. R., Longmore, G., Faccio, R., DeNardo, D. G., & Stewart, S. A. (2016). Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nature Communications, 7(1), 11762. https://doi.org/10.1038/ncomms11762 google scholar
  • Sadaie, M., Salama, R., Carroll, T., Tomimatsu, K., Chandra, T., Young, A. R. J., Narita, M., Pérez-Mancera, P. A., Bennett, D. C., Chong, H., Kimura, H., & Narita, M. (2013). Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence. Genes & Development, 27(16), 1800-1808. https://doi.org/10.1101/gad.217281.113 google scholar
  • Sagiv, A., Burton, D. G. A., Moshayev, Z., Vadai, E., Wensveen, F., Ben-Dor, S., Golani, O., Polic, B., & Krizhanovsky, V. (2016). NKG2D ligands mediate immunosurveillance of senescent cells. Aging (Albany NY), 8(2), 328-344. https://doi.org/10.18632/ aging.100897 google scholar
  • Schulz-Heddergott, R., Stark, N., Edmunds, S. J., Li, J., Conradi, L.-C., Bohnenberger, H., Ceteci, F., Greten, F. R., Dobbelstein, M., & Moll, U. M. (2018). Therapeutic ablation of gain-of-function mutant p53 in colorectal cancer inhibits Stat3- mediated tumor growth and invasion. Cancer Cell, 34(2), 298-314. https://doi. org/10.1016/j.ccell.2018.07.004 google scholar
  • Selvam, S. P., Roth, B. M., Nganga, R., Kim, J., Cooley, M. A., Helke, K., Smith, C. D., & Ogretmen, B. (2018). Balance between senescence and apoptosis is regulated by telomere damage–induced association between p16 and caspase-3. Journal of Biological Chemistry, 293(25), 9784-9800. https://doi.org/10.1074/jbc.RA118. 003506 google scholar
  • Sharma, R., & Padwad, Y. (2019). In search of nutritional anti-aging targets: TOR inhibitors, SASP modulators, and BCL-2 family suppressors. Nutrition, 65, 33-38. https://doi.org/10.1016/j.nut.2019.01.020 google scholar
  • Sheekey, E., & Narita, M. (2023). p53 in senescence–it's a marathon, not a sprint. The FEBS journal, 290(5), 1212-1220. https://doi.org/10.1111/febs.16325 google scholar
  • Sherr, C. J., & Roberts, J. M. (1999). CDK inhibitors: positive and negative regulators of G1-phase progression. Genes & development, 13(12), 1501-1512. Retrieved from https://pubmed.ncbi.nlm.nih.gov/10385618/ google scholar
  • Shin, E., Jung, W. H., & Koo, J. S. (2015). Expression of p16 and pRB in invasive breast cancer. International Journal of Clinical and Experimental Pathology, 8(7), 8209-8217. Retrieved from https://pmc.ncbi.nlm.nih.gov/articles/PMC4555717/ google scholar
  • Slingerland, J., & Pagano, M. (2000). Regulation of the cdk inhibitor p27 and its deregulation in cancer. Journal of Cellular Physiology, 183(1), 10-17. https://doi. org/10.1002/(sici)1097-4652(200004)183:1%3C10::aid-jcp2%3E3.0.co;2-i google scholar
  • Slobodnyuk, K., Radic, N., Ivanova, S., Llado, A., Trempolec, N., Zorzano, A., & Nebreda, A. R. (2019). Autophagy-induced senescence is regulated by p38α signaling. Cell Death & Disease, 10(6), 376. https://doi.org/10.1038/s41419-019-1607-0 google scholar
  • Sobecki, M., Mrouj, K., Camasses, A., Parisis, N., Nicolas, E., Lle` res, D., Gerbe, F., Prieto, S., Krasinska, L., David, A., Eguren, M., Birling, M.-C., Urbach, S., Hem, S., De´ jardin, J., Malumbres, M., Jay, P., Dulic, V., Lafontaine, D. L. J., … & Fisher, D. (2016). The cell proliferation antigen Ki-67 organises heterochromatin. Elife, 5, e13722. https://doi.org/10.7554/eLife.13722 google scholar
  • Sobecki, M., Mrouj, K., Colinge, J., Gerbe, F., Jay, P., Krasinska, L., Dulic, V., & Fisher, D. (2017). Cell-cycle regulation accounts for variability in Ki-67 expression levels. Cancer Research, 77(10), 2722-2734. https://doi.org/10.1158/0008-5472. CAN-16-0707 google scholar
  • Sousa-Victor, P., Gutarra, S., García-Prat, L., Rodriguez-Ubreva, J., Ortet, L., Ruiz-Bonilla, V., Jardí, M., Ballestar, E., González, S., Serrano, A. L., Perdiguero, E., & Muñoz- Cánoves, P. (2014). Geriatric muscle stem cells switch reversible quiescence into senescence. Nature, 506(7488), 316-321. https://doi.org/10.1038/nature 13013 google scholar
  • Storer, M., Mas, A., Robert-Moreno, A., Pecoraro, M., Ortells, M. C., Di Giacomo, V., Yosef, R., Pilpel, N., Krizhanovsky, V., Sharpe, J., & Keyes, W. M. (2013). Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell, 155(5), 1119-1130. https://doi.org/10.1016/j.cell.2013.10.041 google scholar
  • Suda, M., Shimizu, I., Katsuumi, G., Hsiao, C. L., Yoshida, Y., Matsumoto, N., Yoshida, Y., Katayama, A., Wada, J., Seki, M., Suzuki, Y., Okuda, S., Ozaki, K., Nakanishi-Matsui, M., & Minamino, T. (2022). Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Scientific Reports, 12(1), 6522. https://doi.org/10.1038/s41598-022-10522-3 google scholar
  • Sun, H., Wang, H., Wang, X., Aoki, Y., Wang, X., Yang, Y., Cheng, X., Wang, Z., & Wang, X. (2020). Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Theranostics, 10(15), 6928-6945. https:// doi.org/10.7150/thno.43811 google scholar
  • Sun, X., Bizhanova, A., Matheson, T. D., Yu, J., Zhu, L. J., & Kaufman, P. D. (2017). Ki-67 contributes to normal cell cycle progression and inactive X heterochromatin in p21 checkpoint-proficient human cells. Molecular and cellular biology, 37(17), e00569-16. https://doi.org/10.1128/mcb.00569-16 google scholar
  • Sun, Z., Chen, H., & Liu, Y. (2023). Influence of Oxa-Nano-Liposome on the Drug Resistance of Gastric Cancer Cells Under p53-Mediated Autophagy. Science of Advanced Materials, 15(11), 1525-1533. https://doi.org/10.1166/sam.2023.4544 google scholar
  • Swanson, E. C., Manning, B., Zhang, H., & Lawrence, J. B. (2013). Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence. Journal of Cell Biology, 203(6), 929-942. https://doi.org/10.1083/ jcb.201306073 google scholar
  • Swat, A., Dolado, I., Rojas, J. M., & Nebreda, A. R. (2009). Cell density-dependent inhibition of epidermal growth factor receptor signaling by p38α mitogen- activated protein kinase via Sprouty2 downregulation. Molecular and Cellular Biology, 29(12), 3332-3343. https://doi.org/10.1128/MCB.01955-08 google scholar
  • Tanaka, T., Narazaki, M., & Kishimoto, T. (2014). IL-6 in inflammation, immunity, and disease. Cold Spring Harbor Perspectives in Biology, 6(10), a016295. https:// doi.org/10.1101/cshperspect.a016295 google scholar
  • Tang, H., Fan, X., Xing, J., Liu, Z., Jiang, B., Dou, Y., Gorospe, M., & Wang, W. (2015). NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation. Aging (Albany NY), 7(12), 1143-1155. https://doi.org/ 10.18632/aging.100860 google scholar
  • Tang, Y., Zhao, W., Chen, Y., Zhao, Y., & Gu, W. (2008). Acetylation is indispensable for p53 activation. Cell, 133(4), 612-626. https://doi.org/10.1016/j.cell.2008.03.025 google scholar
  • Teo, Y. V., Rattanavirotkul, N., Olova, N., Salzano, A., Quintanilla, A., Tarrats, N., Kiourtis, C., Müller, M., Green, A. R., Adams, P. D., Acosta, J.-C., Bird, T. G., Kirschner, K., Neretti, N., & Chandra, T. (2019). Notch signaling mediates secondary senes- cence. Cell Reports, 27(4), 997-1007. https://doi.org/10.1016/j.celrep.2019.03.104 google scholar
  • Terzi, M. Y., Izmirli, M., & Gogebakan, B. (2016). The cell fate: senescence or quies- cence. Molecular Biology Reports, 43, 1213-1220. http://dx.doi.org/10.1007%2Fs 11033-016-4065-0 google scholar
  • Thangavel, C., Boopathi, E., Liu, Y., McNair, C., Haber, A., Perepelyuk, M., Bhardwaj, A., Addya, S., Ertel, A., Shoyele, S., Birbe, R., Salvino, J. M., Dicker, A. P., Knudsen, K. google scholar
  • E., & Den, R. B. (2018). Therapeutic challenge with a CDK 4/6 inhibitor induces an RB-dependent SMAC-mediated apoptotic response in non–small cell lung cancer. Clinical Cancer Research, 24(6), 1402-1414. https://doi.org/10.1158/1078- 0432.CCR-17-2074 google scholar
  • Thangavel, C., Dean, J. L., Ertel, A., Knudsen, K. E., Aldaz, C. M., Witkiewicz, A. K., Clarke, R., & Knudsen, E. S. (2011). Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocrine-related Cancer, 18(3), 333-345. https://doi.org/10.1530/ERC-10-0262 google scholar
  • Thoms, H. C., Dunlop, M. G., & Stark, L. A. (2007). p38-mediated inactivation of cyclin D1/cyclin-dependent kinase 4 stimulates nucleolar translocation of RelA and apoptosis in colorectal cancer cells. Cancer Research, 67(4), 1660-1669. https:// doi.org/10.1158/0008-5472.CAN-06-1038 google scholar
  • Tonnessen-Murray, C. A., Frey, W. D., Rao, S. G., Shahbandi, A., Ungerleider, N. A., Olayiwola, J. O., Murray, L. B., Vinson, B. T., Chrisey, D. B., Lord, C. J., & Jackson, J. G. (2019). Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival. Journal of Cell Biology, 218(11), 3827-3844. https://doi. org/10.1083/jcb.201904051 google scholar
  • Triana-Martínez, F., Loza, M. I., & Domínguez, E. (2020). Beyond tumor suppression: senescence in cancer stemness and tumor dormancy. Cells, 9(2), 346. https:// doi.org/10.3390/cells9020346 google scholar
  • Truskowski, K., Amend, S. R., & Pienta, K. J. (2023). Dormant cancer cells: programmed quiescence, senescence, or both?. Cancer and Metastasis Reviews, 42(1), 37-47. https://doi.org/10.1007/s10555-022-10073-z google scholar
  • Valieva, Y., Ivanova, E., Fayzullin, A., Kurkov, A., & Igrunkova, A. (2022). Senescence- associated β-galactosidase detection in pathology. Diagnostics, 12(10), 2309. https://doi.org/10.3390/diagnostics12102309 google scholar
  • van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446. https://doi.org/10.1038/nature13193 google scholar
  • Vilgelm, A. E., Johnson, C. A., Prasad, N., Yang, J., Chen, S.-C., Ayers, G. D., Pawlikowski, J. S., Raman, D., Sosman, J. A., Kelley, M., Ecsedy, J. A., Shyr, Y., Levy, S. E., & Richmond, A. (2016). Connecting the dots: therapy-induced senescence and a tumor-suppressive immune microenvironment. Journal of the National Cancer Institute, 108(6), djv406. https://doi.org/10.1093/jnci/djv406 google scholar
  • Wagner, J., Damaschke, N., Yang, B., Truong, M., Guenther, C., McCormick, J., Huang, W., & Jarrard, D. (2015). Overexpression of the novel senescence marker β- galactosidase (GLB1) in prostate cancer predicts reduced PSA recurrence. PloS One, 10(4), e0124366. https://doi.org/10.1371/journal.pone.0124366 google scholar
  • Wakita, M., Takahashi, A., Sano, O., Loo, T. M., Imai, Y., Narukawa, M., Iwata, H., Matsu- daira, T., Kawamoto, S., Ohtani, N., Yoshimori, T., & Hara, E. (2020). A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells. Nature Communications, 11(1), 1935. https://doi.org/10.1038/s 41467-020-15719-6 google scholar
  • Wander, S. A., Zhao, D., Besser, A. H., Hong, F., Wei, J., Ince, T. A., Milikowski, C., Bish- opric, N. H., Minn, A. J., Creighton, C. J., & Slingerland, J. M. (2013). PI3K/mTOR inhibition can impair tumor invasion and metastasis in vivo despite a lack of antiproliferative action in vitro: implications for targeted therapy. Breast Cancer Research and Treatment, 138, 369-381. https://doi.org/10.1007/s10549- 012-2389-6 google scholar
  • Wang, B., Varela-Eirin, M., Brandenburg, S. M., Hernandez-Segura, A., van Vliet, T., Jongbloed, E. M., Wilting, S. M., Ohtani, N., Jager, A., & Demaria, M. (2020). Phar- macological CDK4/6 inhibition unravels a p53-induced secretory phenotype in senescent cells. bioRxiv. https://doi.org/10.1101/2020.06.05.135715 google scholar
  • Wang, H., Grand, R. J., Milner, A. E., Armitage, R. J., Gordon, J., & Gregory, C. D. (1996). Re- pression of apoptosis in human B-lymphoma cells by CD40-ligand and Bcl-2: relationship to the cell-cycle and role of the retinoblastoma protein. Oncogene, 13(2), 373-379. Retrieved from https://pubmed.ncbi.nlm.nih.gov/8710376/ google scholar
  • Wang, H., Zhu, L. J., Yang, Y. C., Wang, Z. X., & Wang, R. (2014). MiR-224 promotes the chemoresistance of human lung adenocarcinoma cells to cisplatin via regulating G1/S transition and apoptosis by targeting p21WAF1/CIP1. British Journal of Cancer, 111(2), 339-354. https://doi.org/10.1038/bjc.2014.157 google scholar
  • Wang, L., Lankhorst, L., & Bernards, R. (2022). Exploiting senescence for the treatment of cancer. Nature Reviews Cancer, 22(6), 340-355. https://doi.org/10.1038/s 41568-022-00450-9 google scholar
  • Wang, R. H., Liu, C. W., Avramis, V. I., & Berndt, N. (2001). Protein phosphatase 1α- mediated stimulation of apoptosis is associated with dephosphorylation of the retinoblastoma protein. Oncogene, 20(43), 6111-6122. https://doi.org/10. 1038/sj.onc.1204829 google scholar
  • Wang, Z., Zhan, Y., Xu, J., Wang, Y., Sun, M., Chen, J., Liang, T., Wu, L., & Xu, K. (2020). β-sitosterol reverses multidrug resistance via BCRP suppression by inhibiting the p53–MDM2 interaction in colorectal cancer. Journal of Agricultural and Food Chemistry, 68(12), 3850-3858. https://doi.org/10.1021/acs.jafc.0c00107 google scholar
  • Watanabe, A., Suzuki, H., Yokobori, T., Tsukagoshi, M., Altan, B., Kubo, N., Suzuki, S., Araki, K., Wada, S., Kashiwabara, K., Hosouchi, Y., & Kuwano, H. (2014). Stathmin1 regulates p27 expression, proliferation and drug resistance, resulting in poor clinical prognosis in cholangiocarcinoma. Cancer Science, 105(6), 690-696. https://doi.org/10.1111/cas.12417 google scholar
  • Webber, J. L., & Tooze, S. A. (2010). Coordinated regulation of autophagy by p38α MAPK through mAtg9 and p38IP. The EMBO Journal, 29(1), 27-40. https://doi.org/10. 1038/emboj.2009.321 google scholar
  • Witkiewicz, A. K., Chung, S., Brough, R., Vail, P., Franco, J., Lord, C. J., & Knudsen, E. S. (2018). Targeting the vulnerability of RB tumor suppressor loss in triple- negative breast cancer. Cell Reports, 22(5), 1185-1199. https://doi.org/10.1016/j. celrep.2018.01.022 google scholar
  • Wu, B., Ueno, M., Onodera, M., Kusaka, T., Huang, C.-l., Hosomi, N., Kanenishi, K., & Sakamoto, H. (2009). Age-related changes in P-glycoprotein expression in senescence-accelerated mouse. Current Aging Science, 2(3), 187-192. google scholar
  • Wu, M. F., Huang, Y. H., Chiu, L. Y., Cherng, S. H., Sheu, G. T., & Yang, T. Y. (2022). Curcumin induces apoptosis of chemoresistant lung cancer cells via ROS-regulated p38 MAPK phosphorylation. International Journal of Molecular Sciences, 23(15), 8248. https://doi.org/10.3390/ijms23158248 google scholar
  • Xiao, Y., Liang, M. R., Liu, C. C., Wang, Y. N., Zeng, Y., Zhou, J., Zhu, H.T., Wang, Q., Zou, Y., & Zeng, S. Y. (2019). Overexpression of P16 reversed the MDR1-mediated DDP resistance in the cervical adenocarcinoma by activating the ERK1/2 signaling pathway. Cell Division, 14, 1-10. https://doi.org/10.1186/s13008-019-0048-6 google scholar
  • Xu, B., Jia, Q., Liao, X., Fan, T., Mou, L., Song, Y., Zhu, C., Yang, T., Li, Z., Wang, M., Zhang, Q., & Liang, L. (2024). Inositol hexaphosphate enhances chemotherapy by reversing senescence induced by persistently activated PERK and diph- thamide modification of eEF2. Cancer Letters, 582, 216591. https://doi.org/10. 1016/j.canlet.2023.216591 google scholar
  • Xu, J., Shi, J., Tang, W., Jiang, P., Guo, M., Zhang, B., & Ma, G. (2020). ROR2 promotes the epithelial‐mesenchymal transition by regulating MAPK/p38 signaling pathway in breast cancer. Journal of Cellular Biochemistry, 121(10), 4142-4153. https:// doi.org/10.1002/jcb.29666 google scholar
  • Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon- Cardo, C., & Lowe, S. W. (2007). Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature, 445(7128), 656-660. https://doi.org/10.1038/nature05529 google scholar
  • Yang, H. W., Chung, M., Kudo, T., & Meyer, T. (2017). Competing memories of mitogen and p53 signalling control cell-cycle entry. Nature, 549(7672), 404-408. https:// doi.org/10.1038/nature23880 google scholar
  • Yao, J., Huang, A., Zheng, X., Liu, T., Lin, Z., Zhang, S., Yang, Q., Zhang, T., & Ma, H. (2017). 53BP1 loss induces chemoresistance of colorectal cancer cells to 5-fluorouracil by inhibiting the ATM–CHK2–P53 pathway. Journal of Cancer Research and Clinical Oncology, 143, 419-431. https://doi.org/10.1007/s00432-016-2302-5 google scholar
  • You, H., Yamamoto, K., & Mak, T. W. (2006). Regulation of transactivation-independent proapoptotic activity of p53 by FOXO3a. Proceedings of the National Academy of Sciences, 103(24), 9051-9056. https://doi.org/10.1073/pnas.0600889103 google scholar
  • Yu, D.-M., Jung, S. H., An, H.-T., Lee, S., Hong, J., Park, J. S., Lee, H., Lee, H., Bahn, M.-S., Lee, H. C., Han, N.-K., Ko, J., Lee, J.-S., & Ko, Y.-G. (2017). Caveolin‐1 defi- ciency induces premature senescence with mitochondrial dysfunction. Aging Cell, 16(4), 773-784. https://doi.org/10.1111/acel.12606 google scholar
  • Yu, W., Imoto, I., Inoue, J., Onda, M., Emi, M., & Inazawa, J. (2007). A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity. Oncogene, 26(8), 1178-1187. https://doi.org/10.1038/sj.onc. 1209899 google scholar
  • Yu, Y., Schleich, K., Yue, B., Ji, S., Lohneis, P., Kemper, K., Silvis, M. R., Qutob, N., van Rooijen, E., Werner-Klein, M., Li, L., Dhawan, D., Meierjohann, S., Reimann, M., google scholar
  • Elkahloun, A., Treitschke, S., Dörken, B., Speck, C., Mallette, F. A., … & Lee, S. (2018). Targeting the senescence-overriding cooperative activity of struc- turally unrelated H3K9 demethylases in melanoma. Cancer Cell, 33(2), 322-336. https://doi.org/10.1016/j.ccell.2018.01.002 google scholar
  • Yuan, B., El Dana, F., Ly, S., Yan, Y., Ruvolo, V., Shpall, E. J., Konopleva, M., Andreeff, M., & Battula, V. L. (2020a). Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance therapy resistance in AML through a TGF-β-p38-ALDH2 pathway. PLoS One, 15(11), e0242809. https://doi.org/10.1371/ journal.pone.0242809 google scholar
  • Yuan, X., Liu, Y., Bijonowski, B. M., Tsai, A.-C., Fu, Q., Logan, T. M., Ma, T., & Li, Y. (2020b). NAD+/NADH redox alterations reconfigure metabolism and rejuvenate senes- cent human mesenchymal stem cells in vitro. Communications Biology, 3(1), 774. https://doi.org/10.1038/s42003-020-01514-y google scholar
  • Zeng, C. Y., Yang, T. T., Zhou, H. J., Zhao, Y., Kuang, X., Duan, W., & Du, J. R. (2019). Lentiviral vector–mediated overexpression of Klotho in the brain improves Alzheimer's disease–like pathology and cognitive deficits in mice. Neurobiology of Aging, 78, 18-28. https://doi.org/10.1016/j.neurobiolaging.2019.02.003 google scholar
  • Zhang, H., Stallock, J. P., Ng, J. C., Reinhard, C., & Neufeld, T. P. (2000). Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes & development, 14(21), 2712-2724. https://doi.org/10.1101/gad.835000 google scholar
  • Zhao, G., Wang, H., Xu, C., Wang, P., Chen, J., Wang, P., Sun, Z., Su, Y., Wang, Z., Han, L., & Tong, T. (2016). SIRT6 delays cellular senescence by promoting p27Kip1 ubiqui- tin-proteasome degradation. Aging (Albany NY), 8(10), 2308-2323. https://doi. org/10.18632/aging.101038 google scholar
  • Zhao, S., Wang, L., Ouyang, M., Xing, S., Liu, S., Sun, L., & Yu, H. (2024). Polyploid giant cancer cells induced by Docetaxel exhibit a senescence phenotype with the expression of stem cell markers in ovarian cancer cells. Plos One, 19(7), e0306969. https://doi.org/10.1371/journal.pone.0306969 google scholar
  • Zhao, Y. F., Zhao, J. Y., Yue, H., Hu, K. S., Shen, H., Guo, Z. G., & Su, X. J. (2015). FOXD1 pro- motes breast cancer proliferation and chemotherapeutic drug resistance by targeting p27. Biochemical and Biophysical Research Communications, 456(1), 232-237. https://doi.org/10.1016/j.bbrc.2014.11.064 google scholar
  • Zhou, W., Wang, J., Qi, Q., Feng, Z., Huang, B., Chen, A., Zhang, D., Li, W., Zhang, Q., Bjerkvig, R., Li, X., & Wang, J. (2018). Matrine induces senescence of human glioblastoma cells through suppression of the IGF1/PI3K/AKT/p27 signaling pathway. Cancer Medicine, 7(9), 4729-4743. https://doi.org/10.1002/cam4.1720 google scholar
There are 237 citations in total.

Details

Primary Language English
Subjects Pharmaceutical Biochemistry
Journal Section Review
Authors

Buket Hün 0000-0003-4718-6597

Pınar Aksoy Sağırlı 0000-0002-9432-3163

Publication Date September 23, 2025
Submission Date December 19, 2024
Acceptance Date January 27, 2025
Published in Issue Year 2025 Volume: 55 Issue: 2

Cite

APA Hün, B., & Aksoy Sağırlı, P. (2025). Current Biomarkers of Cellular Senescence: Mechanistic Insights and Their Implications for Drug Resistance in Cancer. İstanbul Journal of Pharmacy, 55(2), 301-317. https://doi.org/10.26650/IstanbulJPharm.2025.1603560
AMA Hün B, Aksoy Sağırlı P. Current Biomarkers of Cellular Senescence: Mechanistic Insights and Their Implications for Drug Resistance in Cancer. iujp. September 2025;55(2):301-317. doi:10.26650/IstanbulJPharm.2025.1603560
Chicago Hün, Buket, and Pınar Aksoy Sağırlı. “Current Biomarkers of Cellular Senescence: Mechanistic Insights and Their Implications for Drug Resistance in Cancer”. İstanbul Journal of Pharmacy 55, no. 2 (September 2025): 301-17. https://doi.org/10.26650/IstanbulJPharm.2025.1603560.
EndNote Hün B, Aksoy Sağırlı P (September 1, 2025) Current Biomarkers of Cellular Senescence: Mechanistic Insights and Their Implications for Drug Resistance in Cancer. İstanbul Journal of Pharmacy 55 2 301–317.
IEEE B. Hün and P. Aksoy Sağırlı, “Current Biomarkers of Cellular Senescence: Mechanistic Insights and Their Implications for Drug Resistance in Cancer”, iujp, vol. 55, no. 2, pp. 301–317, 2025, doi: 10.26650/IstanbulJPharm.2025.1603560.
ISNAD Hün, Buket - Aksoy Sağırlı, Pınar. “Current Biomarkers of Cellular Senescence: Mechanistic Insights and Their Implications for Drug Resistance in Cancer”. İstanbul Journal of Pharmacy 55/2 (September2025), 301-317. https://doi.org/10.26650/IstanbulJPharm.2025.1603560.
JAMA Hün B, Aksoy Sağırlı P. Current Biomarkers of Cellular Senescence: Mechanistic Insights and Their Implications for Drug Resistance in Cancer. iujp. 2025;55:301–317.
MLA Hün, Buket and Pınar Aksoy Sağırlı. “Current Biomarkers of Cellular Senescence: Mechanistic Insights and Their Implications for Drug Resistance in Cancer”. İstanbul Journal of Pharmacy, vol. 55, no. 2, 2025, pp. 301-17, doi:10.26650/IstanbulJPharm.2025.1603560.
Vancouver Hün B, Aksoy Sağırlı P. Current Biomarkers of Cellular Senescence: Mechanistic Insights and Their Implications for Drug Resistance in Cancer. iujp. 2025;55(2):301-17.