Roscovitine inhibits glycogen synthase kinase 3 beta signaling and exerts apoptotic effect with an increase in reactive oxygen species generation in neuroblastoma cells

Year 2023, Volume: 40 Issue: 4, 755 - 767, 03.01.2024

Zeynep Demirel , Esranur Kopal , Nilay Dinckurt , Berkay Gürkan , Ayse Keskin Gunay , Elif Damla Arısan , Pınar Obakan Yerlikaya

Abstract

Roscovitine (ROSC) is a selective cyclin-dependent kinase (CDK) inhibitor against CDK2, 7 and 9. The anti-proliferative and anti-cancer activities of ROSC have been well-documented in both in vivo and in vitro studies against several cancer types. Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase having role in the regulation of glycogen synthase. It also has a role in multiple cellular processes as well as disease conditions. A member of the GSK3 family, GSK3β, has been implicated in many human malignancies including neuroblastoma. The specific inhibition of GSK3β was responsible for reducing neuroendocrine markers and suppressing neuroblastoma (NB) cell growth. NB is a malign pediatric disease with diverse types of tumors and high heterogeneity. Lately, GSK3β targeted therapy models are being investigated for NB therapy. The action of ROSC on GSK3β, however, is not fully understood. In this study, we showed that ROSC exerts anti-proliferative and apoptotic activity in SK-N-AS neuroblastoma cells by increasing reactive oxygen species (ROS) generation, which can be prevented by N-acetyl-cysteine administration. ROSC treatment inhibited GSK3β signaling by promoting Ser9 inhibitory phosphorylation. Together, ROSC at low doses can be a drug candidate to modulate GSK3β signaling in NB cells.

Keywords

Neuroblastoma, roscovitine, cell cycle, apoptosis, GSK3β

Thanks

We are grateful to İstanbul Kultur University and İstanbul Medeniyet University, Science and Advanced Technologies Research Center (IMU-BILTAM) where the research was conducted.

References

• 1. Van Arendonk KJ, Chung DH. Neuroblastoma: Tumor Biology and Its Implications for Staging and Treatment. Children (Basel). 2019 Jan 17;6(1).
• 2. Barr EK, Applebaum MA. Genetic Predisposition to Neuroblastoma. Children (Basel). 2018 Aug 31;5(9).
• 3. Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Hematol Oncol Clin North Am. 2010 Feb;24(1):65–86.
• 4. Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010 Jun 10;362(23):2202–11.
• 5. Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003 Mar;3(3):203–16.
• 6. Yue ZX, Huang C, Gao C, Xing TY, Liu SG, Li XJ, et al. MYCN amplification predicts poor prognosis based on interphase fluorescence in situ hybridization analysis of bone marrow cells in bone marrow metastases of neuroblastoma. Cancer Cell Int [Internet]. 2017 Mar 31 [cited 2023 Jul 24];17(1):43. Available from: /pmc/articles/PMC5374581/
• 7. Trigg RM, Turner SD. ALK in Neuroblastoma: Biological and Therapeutic Implications. Cancers (Basel) [Internet]. 2018 Apr 1 [cited 2023 Jul 24];10(4). Available from: /pmc/articles/PMC5923368/
• 8. J Ribelles A, Barberá S, Yáñez Y, Gargallo P, Segura V, Juan B, et al. Clinical Features of Neuroblastoma with 11q Deletion: An Increase in Relapse Probabilities in Localized and 4S Stages. Scientific Reports 2019 9:1 [Internet]. 2019 Sep 24 [cited 2023 Jul 24];9(1):1–9. Available from: https://www.nature.com/articles/s41598-019-50327-5
• 9. Attiyeh EF, London WB, Mossé YP, Wang Q, Winter C, Khazi D, et al. Chromosome 1p and 11q Deletions and Outcome in Neuroblastoma. New England Journal of Medicine. 2005 Nov 24;353(21):2243–53.
• 10. Duffy DJ, Krstic A, Schwarzl T, Higgins DG, Kolch W. GSK3 inhibitors regulate MYCN mRNA levels and reduce neuroblastoma cell viability through multiple mechanisms, including p53 and Wnt signaling. Mol Cancer Ther [Internet]. 2014 Feb 1 [cited 2023 Jul 24];13(2):454–67. Available from: https://dx.doi.org/10.1158/1535-7163.MCT-13-0560-T
• 11. Dickey A, Schleicher S, Leahy K, Hu R, Hallahan D, Thotala DK. GSK-3β inhibition promotes cell death, apoptosis, and in vivo tumor growth delay in neuroblastoma Neuro-2A cell line. J Neurooncol. 2011 Aug;104(1):145–53.
• 12. Kunnimalaiyaan S, Schwartz VK, Jackson IA, Clark Gamblin T, Kunnimalaiyaan M. Antiproliferative and apoptotic effect of LY2090314, a GSK-3 inhibitor, in neuroblastoma in vitro. BMC Cancer [Internet]. 2018 May 11 [cited 2023 Jul 24];18(1):1–8. Available from: https://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-4474-7
• 13. Wu YY, Hsieh CT, Chiu YM, Chou SC, Kao JT, Shieh DC, et al. GSK-3 inhibitors enhance TRAIL-mediated apoptosis in human gastric adenocarcinoma cells. PLoS One [Internet]. 2018 Dec 1 [cited 2023 Jul 24];13(12). Available from: /pmc/articles/PMC6296518/
• 14. Li H, Huang K, Liu X, Liu J, Lu X, Tao K, et al. Lithium Chloride Suppresses Colorectal Cancer Cell Survival and Proliferation through ROS/GSK-3í µí»½/NF-í µí¼ B Signaling Pathway. 2014 [cited 2023 Jul 24]; Available from: http://dx.doi.org/10.1155/2014/241864
• 15. Wang Y, Zhang Q, Wang B, Li · Peng, Liu · Pinan. LiCl Treatment Induces Programmed Cell Death of Schwannoma Cells through AKT- and MTOR-Mediated Necroptosis. Neurochem Res. 2017;3:2363–71.
• 16. Wang L, Li J, Di L jun. Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases. Med Res Rev [Internet]. 2022 Mar 1 [cited 2023 Jul 24];42(2):946. Available from: /pmc/articles/PMC9298385/
• 17. Hur EM, Zhou FQ. GSK3 signaling in neural development. Nat Rev Neurosci [Internet]. 2010 Aug [cited 2023 Jul 24];11(8):539. Available from: /pmc/articles/PMC3533361/
• 18. Valenta T, Hausmann G, Basler K. The many faces and functions of β-catenin. EMBO J [Internet]. 2012 Jun 6 [cited 2023 Jul 24];31(12):2714. Available from: /pmc/articles/PMC3380220/
• 19. Tejeda-Muñoz N, Robles-Flores M. Glycogen synthase kinase 3 in Wnt signaling pathway and cancer. IUBMB Life [Internet]. 2015 Dec 1 [cited 2023 Jul 24];67(12):914–22. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/iub.1454
• 20. Fernandes JC, Rodrigues Alves APN, Machado-Neto JA, Scopim-Ribeiro R, Fenerich BA, da Silva FB, et al. IRS1/β-Catenin Axis Is Activated and Induces MYC Expression in Acute Lymphoblastic Leukemia Cells. J Cell Biochem [Internet]. 2017 Jul 1 [cited 2023 Jul 24];118(7):1774–81. Available from: https://pubmed.ncbi.nlm.nih.gov/27987331/
• 21. Jacobs KM, Bhave SR, Ferraro DJ, Jaboin JJ, Hallahan DE, Thotala D. GSK-3β: A Bifunctional Role in Cell Death Pathways. Int J Cell Biol [Internet]. 2012 [cited 2023 Jul 24];2012. Available from: /pmc/articles/PMC3364548/
• 22. Delehouzé C, Godl K, Loaëc N, Bruyère C, Desban N, Oumata N, et al. CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells. Oncogene. 2014 Dec 11;33(50):5675–87.
• 23. Bettayeb K, Baunbæk D, Delehouze C, Loaëc N, Hole AJ, Baumli S, et al. CDK Inhibitors Roscovitine and CR8 Trigger Mcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma Cells. Genes Cancer. 2010 Apr;1(4):369–80.
• 24. Chen Z, Wang Z, Pang JC, Yu Y, Bieerkehazhi S, Lu J, et al. Multiple CDK inhibitor dinaciclib suppresses neuroblastoma growth via inhibiting CDK2 and CDK9 activity. Sci Rep. 2016 Jul 5;6:29090.
• 25. Huang Q, Zhong Y, Li J, Ye Y, Wu W, Chen L, et al. Kinase inhibitor roscovitine as a PB2 cap-binding inhibitor against influenza a virus replication. Biochem Biophys Res Commun. 2020 Jun 11;526(4):1143–9.
• 26. Le Roy L, Letondor A, Le Roux C, Amara A, Timsit S. Cellular and Molecular Mechanisms of R/S-Roscovitine and CDKs Related Inhibition under Both Focal and Global Cerebral Ischemia: A Focus on Neurovascular Unit and Immune Cells. Cells. 2021 Jan 8;10(1).
• 27. Jorda R, Paruch K, Krystof V. Cyclin-dependent kinase inhibitors inspired by roscovitine: purine bioisosteres. Curr Pharm Des. 2012;18(20):2974–80.
• 28. Bukanov NO, Moreno SE, Natoli TA, Rogers KA, Smith LA, Ledbetter SR, et al. CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD. Cell Cycle. 2012 Nov 1;11(21):4040–6.
• 29. Meijer L, Raymond E. Roscovitine and other purines as kinase inhibitors. From starfish oocytes to clinical trials. Acc Chem Res. 2003 Jun;36(6):417–25.
• 30. Le Moigne V, Rodriguez Rincon D, Glatigny S, Dupont CM, Langevin C, Ait Ali Said A, et al. Roscovitine Worsens Mycobacterium abscessus Infection by Reducing DUOX2-mediated Neutrophil Response. Am J Respir Cell Mol Biol. 2022 Apr;66(4):439–51.
• 31. Cicenas J, Kalyan K, Sorokinas A, Stankunas E, Levy J, Meskinyte I, et al. Roscovitine in cancer and other diseases. Ann Transl Med. 2015 Jun;3(10):135.
• 32. Araki T, Liu NA. Cell Cycle Regulators and Lineage-Specific Therapeutic Targets for Cushing Disease. Front Endocrinol (Lausanne). 2018;9:444.
• 33. Tirado OM, Mateo-Lozano S, Notario V. Roscovitine is an effective inducer of apoptosis of Ewing’s sarcoma family tumor cells in vitro and in vivo. Cancer Res. 2005 Oct 15;65(20):9320–7.
• 34. Ryder J, Su Y, Liu F, Li B, Zhou Y, Ni B. Divergent roles of GSK3 and CDK5 in APP processing. Biochem Biophys Res Commun. 2003 Dec 26;312(4):922–9.
• 35. Liu J, Yang J, Xu Y, Guo G, Cai L, Wu H, et al. Roscovitine, a CDK5 Inhibitor, Alleviates Sevoflurane-Induced Cognitive Dysfunction via Regulation Tau/GSK3β and ERK/PPARγ/CREB Signaling. Cell Physiol Biochem. 2017;44(2):423–35.
• 36. Maldonado H, Ramírez E, Utreras E, Pando ME, Kettlun AM, Chiong M, et al. Inhibition of cyclin-dependent kinase 5 but not of glycogen synthase kinase 3-β prevents neurite retraction and tau hyperphosphorylation caused by secretable products of human T-cell leukemia virus type I-infected lymphocytes. J Neurosci Res. 2011 Sep;89(9):1489–98.
• 37. Obakan Yerlikaya P, Arısan ED, Coker Gurkan A, Okumus OO, Yenigun T, Ozbey U, et al. Epibrassinolide prevents tau hyperphosphorylation via GSK3β inhibition in vitro and improves Caenorhabditis elegans lifespan and motor deficits in combination with roscovitine. Amino Acids. 2021 Sep 1;53(9):1373–89.
• 38. Adacan K, Obakan-Yerlikaya P, Arisan ED, Coker-Gurkan A, Kaya RI, Palavan-Unsal N. Epibrassinolide-induced autophagy occurs in an Atg5-independent manner due to endoplasmic stress induction in MEF cells. Amino Acids [Internet]. 2020 Jul 1 [cited 2022 May 12];52(6–7):871–91. Available from: https://pubmed.ncbi.nlm.nih.gov/32449072/
• 39. Obakan-Yerlikaya P, Arisan ED, Coker-Gurkan A, Adacan K, Ozbey U, Somuncu B, et al. Calreticulin is a fine tuning molecule in epibrassinolide-induced apoptosis through activating endoplasmic reticulum stress in colon cancer cells. Mol Carcinog [Internet]. 2017 Jun 1 [cited 2022 May 12];56(6):1603–19. Available from: https://pubmed.ncbi.nlm.nih.gov/28112451/
• 40. Capik O, Gundogdu B, Tatar A, Sahin A, Chen F, Creighton CJ, et al. Oncogenic miR-1825 promotes head and neck carcinogenesis via targeting FREM1. J Cell Biochem [Internet]. 2023 [cited 2023 Sep 19]; Available from: https://pubmed.ncbi.nlm.nih.gov/37683055/
• 41. Li Q, Zhu Z, Zhang H, Wu X, Yang H, Li X, et al. LncRNA RP11-93B14.5 promotes gastric cancer cell growth through PI3K/AKT signaling pathway. Mol Biotechnol [Internet]. 2023 [cited 2023 Sep 19]; Available from: https://pubmed.ncbi.nlm.nih.gov/37682457/
• 42. Coker-Gürkan A, Arisan ED, Obakan P, Akalin K, Özbey U, Palavan-Unsal N. Purvalanol induces endoplasmic reticulum stress-mediated apoptosis and autophagy in a time-dependent manner in HCT116 colon cancer cells. Oncol Rep. 2015 Jun 1;33(6):2761–70.
• 43. Weidner C, Rousseau M, Plauth A, Wowro SJ, Fischer C, Abdel-Aziz H, et al. Iberis amara Extract Induces Intracellular Formation of Reactive Oxygen Species and Inhibits Colon Cancer. PLoS One [Internet]. 2016 Apr 1 [cited 2023 Sep 19];11(4):e0152398. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152398
• 44. Lin S, Lv J, Peng P, Cai C, Deng J, Deng H, et al. Bufadienolides induce p53 mediated apoptosis in esophageal squamous cell carcinoma cells in vitro and in vivo. Oncol Lett. 2018 Feb 1;15(2):1566–72.
• 45. Chen D, Chen C, Huang C, Chen T, Liu Z. Injectable Hydrogel for NIR-II Photo-Thermal Tumor Therapy and Dihydroartemisinin-Mediated Chemodynamic Therapy. Front Chem. 2020 Apr 7;8.
• 46. Obakan P, Arisan ED, Calcabrini A, Agostinelli E, Bolkent Ş, Palavan-Unsal N. Activation of polyamine catabolic enzymes involved in diverse responses against epibrassinolide-induced apoptosis in LNCaP and DU145 prostate cancer cell lines. Amino Acids [Internet]. 2014 [cited 2022 May 12];46(3):553–64. Available from: https://pubmed.ncbi.nlm.nih.gov/23963538/
• 47. Kunnimalaiyaan S, Schwartz VK, Jackson IA, Clark Gamblin T, Kunnimalaiyaan M. Antiproliferative and apoptotic effect of LY2090314, a GSK-3 inhibitor, in neuroblastoma in vitro. BMC Cancer. 2018 May 11;18(1).
• 48. Otte J, Dyberg C, Pepich A, Johnsen JI. MYCN Function in Neuroblastoma Development. Vol. 10, Frontiers in Oncology. Frontiers Media S.A.; 2021.
• 49. Sahin I, Eturi A, De Souza A, Pamarthy S, Tavora F, Giles FJ, et al. Glycogen synthase kinase-3 beta inhibitors as novel cancer treatments and modulators of antitumor immune responses. Vol. 20, Cancer Biology and Therapy. Taylor and Francis Inc.; 2019. p. 1047–56.
• 50. Bahmad HF, Chalhoub RM, Harati H, Bou-Gharios J, Assi S, Ballout F, et al. Tideglusib attenuates growth of neuroblastoma cancer stem/progenitor cells in vitro and in vivo by specifically targeting GSK-3β. Pharmacological Reports. 2021 Feb 1;73(1):211–26.
• 51. Lin J, Song T, Li C, Mao W. GSK-3β in DNA repair, apoptosis, and resistance of chemotherapy, radiotherapy of cancer. Vol. 1867, Biochimica et Biophysica Acta - Molecular Cell Research. Elsevier B.V.; 2020.
• 52. Gonzalez Malagon SG, Liu KJ. ALK and GSK3: Shared Features of Neuroblastoma and Neural Crest Cells. Vol. 12, Journal of Experimental Neuroscience. SAGE Publications Ltd; 2018.
• 53. Yadikar H, Torres I, Aiello G, Kurup M, Yang Z, Lin F, et al. Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization. PLoS One. 2020 Jul 1;15(7 July).
• 54. Le Grand M, Kimpton K, Gana CC, Valli E, Fletcher JI, Kavallaris M. Targeting Functional Activity of AKT Has Efficacy against Aggressive Neuroblastoma. ACS Pharmacol Transl Sci. 2020 Feb 14;3(1):148–60.
• 55. Reinhardt L, Kordes S, Reinhardt P, Glatza M, Baumann M, Drexler HCA, et al. Dual Inhibition of GSK3β and CDK5 Protects the Cytoskeleton of Neurons from Neuroinflammatory-Mediated Degeneration In Vitro and In Vivo. Stem Cell Reports. 2019 Mar 5;12(3):502–17.
• 56. Walz A, Ugolkov A, Chandra S, Kozikowski A, Carneiro BA, O’Halloran T V., et al. Molecular pathways: Revisiting glycogen synthase kinase-3β as a target for the treatment of cancer. Clinical Cancer Research. 2017 Apr 15;23(8):1891–7.
• 57. Teusel F, Henschke L, Mayer TU. Small molecule tools in mitosis research. In: Methods in Cell Biology. Academic Press Inc.; 2018. p. 137–55.
• 58. Meijer L, Borgne A, Mulner O, Chong JPJ, Blow JJ, Inagaki N, et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem. 1997;243(1–2):527–36.
• 59. Kolodziej M, Goetz C, Di Fazio P, Montalbano R, Ocker M, Strik H, et al. Roscovitine has anti-proliferative and pro-apoptotic effects on glioblastoma cell lines: A pilot study. Oncol Rep. 2015 Sep 1;34(3):1549–56.
• 60. Mughal MJ, Bhadresha K, Kwok HF. CDK inhibitors from past to present: A new wave of cancer therapy. Vol. 88, Seminars in Cancer Biology. Academic Press; 2023. p. 106–22.
• 61. Pandey V, Ranjan N, Narne P, Babu PP. Roscovitine effectively enhances antitumor activity of temozolomide in vitro and in vivo mediated by increased autophagy and Caspase-3 dependent apoptosis. Sci Rep. 2019 Dec 1;9(1).
• 62. Arisan ED, Obakan P, Coker A, Palavan-Unsal N. Inhibition of ornithine decarboxylase alters the roscovitine-induced mitochondrial-mediated apoptosis in MCF-7 breast cancer cells. Mol Med Rep. 2012 May;5(5):1323–9.
• 63. Ozfiliz-Kilbas P, Sarikaya B, Obakan-Yerlikaya P, Coker-Gurkan A, Arisan ED, Temizci B, et al. Cyclin-dependent kinase inhibitors, roscovitine and purvalanol, induce apoptosis and autophagy related to unfolded protein response in HeLa cervical cancer cells. Mol Biol Rep. 2018 Oct 1;45(5):815–28.
• 64. Goodyear S, Sharma MC. Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5. Exp Mol Pathol. 2007 Feb;82(1):25–32.
• 65. Roufayel R, Murshid N. CDK5: Key regulator of apoptosis and cell survival. Vol. 7, Biomedicines. MDPI AG; 2019.
• 66. Pizarro JG, Folch J, Junyent F, Verdaguer E, Auladell C, Beas-Zarate C, et al. Antiapoptotic effects of roscovitine on camptothecin-induced DNA damage in neuroblastoma cells. Apoptosis. 2011;16(5):536–50.
• 67. McClue SJ, Blake D, Clarke R, Cowan A, Cummings L, Fischer PM, et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int J Cancer. 2002 Dec 10;102(5):463–8.
• 68. Garrofé-Ochoa X, Cosialls AM, Ribas J, Gil J, Boix J. Transcriptional modulation of apoptosis regulators by roscovitine and related compounds. Apoptosis. 2011 Jul;16(7):660–70.
• 69. Hahntow IN, Schneller F, Oelsner M, Weick K, Ringshausen I, Fend F, et al. Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells. Leukemia. 2004;18(4):747–55.
• 70. Bierbrauer A, Jacob M, Vogler M, Fulda S. A direct comparison of selective BH3-mimetics reveals BCL-XL, BCL-2 and MCL-1 as promising therapeutic targets in neuroblastoma. Br J Cancer. 2020 May 12;122(10):1544–51.
• 71. Klenke S, Akdeli N, Stelmach P, Heukamp L, Schulte JH, Bachmann HS. The small molecule Bcl-2/Mcl-1 inhibitor TW-37 shows single-agent cytotoxicity in neuroblastoma cell lines. BMC Cancer. 2019 Mar 18;19(1).
• 72. Kim EH, Kim SU, Shin DY, Choi KS. Roscovitine sensitizes glioma cells to TRAIL-mediated apoptosis by downregulation of survivin and XIAP. Oncogene. 2004 Jan 15;23(2):446–56.
• 73. Perillo B, Di Donato M, Pezone A, Di Zazzo E, Giovannelli P, Galasso G, et al. ROS in cancer therapy: the bright side of the moon. Vol. 52, Experimental and Molecular Medicine. Springer Nature; 2020. p. 192–203.
• 74. Sandoval R, Lazcano P, Ferrari F, Pinto-Pardo N, González-Billault C, Utreras E. TNF-α increases production of reactive oxygen species through Cdk5 activation in nociceptive neurons. Front Physiol. 2018 Feb 6;9(FEB).
• 75. Yerlikaya PO, Naxmedova S. Epibrassinolide Triggers Apoptotic Cell Death in SK-N-AS Neuroblastoma Cells by Targeting GSK3β in a ROS Generation-Dependent Way. European Journal of Biology. 2022;81(2):240–50.
• 76. Yedjou CG, Tchounwou PB. N-Acetyl-L-Cysteine Affords Protection against Lead-Induced Cytotoxicity and Oxidative Stress in Human Liver Carcinoma (HepG 2 ) Cells [Internet]. Vol. 4, Int. J. Environ. Res. Public Health. 2007. Available from: www.ijerph.org
• 77. Kazi A, Xiang S, Yang H, Delitto D, Trevino J, Jiang RHY, et al. GSK3 suppression upregulates β-catenin and c-Myc to abrogate KRas-dependent tumors. Nat Commun. 2018 Dec 1;9(1).
• 78. Dickey A, Schleicher S, Leahy K, Hu R, Hallahan D, Thotala DK. GSK-3β inhibition promotes cell death, apoptosis, and in vivo tumor growth delay in neuroblastoma Neuro-2A cell line. J Neurooncol. 2011 Aug;104(1):145–53.
• 79. Tompa M, Kalovits F, Nagy A, Kalman B. Contribution of the Wnt Pathway to Defining Biology of Glioblastoma. Vol. 20, NeuroMolecular Medicine. Humana Press Inc.; 2018. p. 437–51.
• 80. Yu WK, Xu ZY, Yuan L, Mo S, Xu B, Cheng XD, et al. Targeting β-Catenin Signaling by Natural Products for Cancer Prevention and Therapy. Front Pharmacol [Internet]. 2020 Jun 30 [cited 2023 Jul 24];11. Available from: /pmc/articles/PMC7338604/
• 81. Park CS, Kim S Il, Lee MS, Youn CY, Kim DJ, Jho EH, et al. Modulation of β-Catenin Phosphorylation/Degradation by Cyclin-dependent Kinase 2. Journal of Biological Chemistry. 2004 May 7;279(19):19592–9.
• 82. Huang CY, Velmurugan BK, Chen MC, Day CH, Chien WS, Padma V V., et al. KHC-4 inhibits β-catenin expression in prostate cancer cells. Biotech Histochem [Internet]. 2019 Jul 4 [cited 2023 Jul 24];94(5):374–80. Available from: https://pubmed.ncbi.nlm.nih.gov/30819007/