NRF2'nin İkili Doğası: Kanser Gelişiminde Koruyucu ve Teşvik Edici Rolü

Year 2024, Volume: 7 Issue: 1, 1 - 16, 30.03.2024

İslim Kaleler İlhan Yaylım

https://doi.org/10.46373/hafebid.1442953

Abstract

Nükleer Faktör Eritroid 2 ile İlişkili Faktör 2 (NRF2), hücrede başlıca oksidatif hasara karşı koruyucu olmakla birlikte metabolizmanın düzenlenmesinde de rolü olan transkripsiyon faktörüdür ve hücresel redoks dengesinin sağlanmasında merkezi rol oynar. Kanserin tedavisi için anahtar mekanizmalardan birisi NRF2 yolağıdır. NRF2-KEAP1 yolağının koruyucu rolleri göz önüne alındığında, aktivasyonunun bir dizi antioksidan mekanizmayı destekleyerek kanser oluşumunu etkili bir şekilde önleyebileceğini düşündürmektedir. Bu nedenle NRF2’nin kanser gelişimindeki ve ilerlemesindeki rolleri yoğun bir şekilde araştırılmaktadır. Başlangıçta kansere karşı koruyucu olduğu ortaya konmasına rağmen, günümüzde kanseri desteklediği de bulunmuştur. Kanserde umut verici terapötik bir hedef olarak görülmekte ve oynadığı “iki yönlü” rolden dolayı NRF2’nin hem aktivatörleri hem de inhibitörleri giderek artan ilgi çekici bir araştırma alanı olmaktadır.

Keywords

NRF2, Oksidatif Stres, Kanser

References

• [1.] De la Vega Rojo, M., Chapman, E., Zhang, D.D., NRF2 and the hallmarks of cancer, Cancer Cell, 34, (2018), 21–43.
• [2.] Vomund, S., Schäfer, A., Parnham, M.J., Brüne, B., von Knethen, A., Nrf2, the master regulator of anti-oxidative responses, Int J Mol Sci, 18, (2017), 2772.
• [3.] Panieri, E., Buha, A., Telkoparan-akillilar, P., Cevik, D., Kouretas, D., et al., Potential applications of NRF2 modulators in cancer therapy, Antioxidants, 9(3), (2020), 1–48.
• [4.] Dodson, M., Rojo de la Vega, M., Cholanians, A.B., Schmidlin, C.J., Chapman, E., et al., Modulating NRF2 in Disease: Timing Is Everything, Annu Rev Pharmacol Toxicol, 59, (2019), 555–75.
• [5.] Panieri, E., Saso, L., Potential applications of NRF2 inhibitors in cancer therapy, Oxid Med Cell Longev, 2019, (2019).
• [6.] Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., et al., An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements, Biochem Biophys Res Commun, 236(2), (1997), 313–22.
• [7.] Tong, K.I., Katoh, Y., Kusunoki, H., Itoh, K., Tanaka, T., et al., Keap1 Recruits Neh2 through Binding to ETGE and DLG Motifs: Characterization of the TwoSite Molecular Recognition Model, Mol Cell Biol, 26(8), (2006), 2887–900.
• [8.] Bono, S., Feligioni, M., Corbo, M., Impaired antioxidant KEAP1-NRF2 system in amyotrophic lateral sclerosis : NRF2 activation as a potential therapeutic strategy, Mol Neurodegener, 16(1), (2021), 71.
• [9.] Bellezza, I., Giambanco, I., Minelli, A., Donato, R., Nrf2-Keap1 signaling in oxidative and reductive stress, BBA - Mol Cell Res, 1865(5), (2018), 721–33.
• [10.]Panieri, E., Buha, A., Telkoparan-akillilar, P., Cevik, D., Kouretas, D., et al., Potential applications of NRF2 modulators in cancer therapy, Antioxidants, 9(3), (2020), 1–48.
• [11.]Telkoparan-Akillilar, P., Suzen, S., Saso, L., Pharmacological applications of Nrf2 inhibitors as potential antineoplastic drugs, Int J Mol Sci, 20(8), (2019).
• [12.]Rojo de la Vega, M., Chapman, E., Zhang, D.D., NRF2 and the Hallmarks of Cancer, Cancer Cell, 34(1), (2018), 21–43.
• [13.]Telkoparan-akillilar, P., Panieri, E., Cevik, D., Suzen, S., Saso, L., Therapeutic Targeting of the NRF2 Signaling Pathway in Cancer, Molecules, 26(5), (2021), 1–17.
• [14.]Suzuki, T., Yamamoto, M., Molecular basis of the Keap1–Nrf2 system, Free Radic Biol Med, 88(Pt B), (2015), 93–100.
• [15.]Rankin, E.B., Giaccia, A.J., Hypoxic control of metastasis, Science (80- ), 352(6282), (2016), 175–80.
• [16.]Ji, X., Wang, H., Zhu, J., Zhu, L., Pan, H., Li, W., et al., Knockdown of Nrf2 suppresses glioblastoma angiogenesis by inhibiting hypoxia-induced activation of HIF-1α, Int J Cancer, 135(3), (2014), 574–84.
• [17.]Oh, E., Kim, J., Kim, J.M., Kim, S.J., Lee, J., Hong, S., et al., NQO1 inhibits proteasome-mediated degradation of HIF-1α, Nat Commun, 7, (2016), 13593.
• [18.]Toth, R.K., Warfel, N.A., Strange Bedfellows: Nuclear Factor, Erythroid 2-Like 2 (Nrf2) and Hypoxia-Inducible Factor 1 (HIF-1) in Tumor Hypoxia, Antioxidants, 6(2), (2017), 27.
• [19.]Fu, J., Xiong, Z., Huang, C., Li, J., Yang, W., et al., Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus, J Biol Chem, 294(1), (2019), 327–40.
• [20.]He, F., Antonucci, L., Karin, M., NRF2 as a regulator of cell metabolism and inflammation in cancer, Carcinogenesis, 41(4), (2020), 405–16.
• [21.]Ludtmann, M.H.R., Angelova, P.R., Zhang, Y., Abramov AY.] Nrf2 affects the efficiency of mitochondrial fatty acid oxidation, Biochem J, 457(3), (2014), 415–24.
• [22.]Denicola, G.M., Chen, P., Mullarky, E., Sudderth, J.A., Wu, D., et al., NRF2 regulates serine biosynthesis in non-small cell lung cancer, Nat Genet, 47(12), (2015), 1475–81.
• [23.]Sayin, V.I., Leboeuf, S.E., Singh, S.X., Davidson, S.M., Biancur, D., et al., Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer, Elife, 6, (2017), e28083.
• [24.]Lau, A., Villeneuve, N.F., Sun, Z., Wong, P.K., Zhang, D.D., Dual Roles of Nrf2 in Cancer, Pharmacol Res, 58 (5–6), (2008), 262–70.
• [25.]Frohlich, D.A., Mccabe, M.T., Arnold, R.S., Day, M.L., The role of Nrf2 in increased reactive oxygen species and DNA damage in prostate tumorigenesis, Oncogene, 27(31), (2008), 4353–62.
• [26.]Cort, A., Ozben, T., Saso, L., Luca, C.De., Korkina, L., Redox Control of Multidrug Resistance and Its Possible Modulation by Antioxidants, Oxid Med Cell Longev, 2016, (2016), 4251912.
• [27.]Shibata, T., Saito, S., Kokubu, A., Suzuki, T., Global Downstream Pathway Analysis Reveals a Dependence of Oncogenic NF-E2 – Related Factor 2 Mutation on the mTOR Growth Signaling Pathway, Cancer Res, 70(22), (2010), 9095–105.
• [28.]Zhang, H.S., Zhang, Z.-G., Du, G.-Y., Sun, H.-L., Liu, H.-Y., et al., Nrf2 promotes breast cancer cell migration via up ‐ regulation of G6PD/HIF‐1α/Notch1 axis, J Cell Mol Med, 23(5), (2019), 3451–63.
• [29.]Rachakonda, G., Sekhar, K.R., Jowhar, D., Samson, P.C., Wikswo, J.P., et al., Increased cell migration and plasticity in Nrf2-deficient cancer cell lines, Oncogene, 29(25), (2010), 3703–14.
• [30.]Sporn, M.B., Liby, K.T., NRF2 and cancer: the good, the bad and the importance of context, Nat Rev cancer, 12(8), (2012), 564–71.
• [31.]Enomoto, A., Itoh, K., Nagayoshi, E., Haruta, J., Kimura, T., et al., High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes, Toxicol Sci, 59(1), (2001), 169–77.
• [32.]Shelton, P., Jaiswal, A.K., The transcription factor NF-E2-related Factor 2 (Nrf2): a protooncogene?, FASEB J, 27(2), (2013), 414–23.
• [33.]Sajadimajd, S., Khazaei, M., Oxidative Stress and Cancer: The Role of Nrf2, Curr Cancer Drug Targets, 18(6), (2018), 538–57.
• [34.]Milkovic, L., Zarkovic, N., Saso, L., Controversy about pharmacological modulation of Nrf2 for cancer therapy, Redox Biol, 12, (2017), 727–32.
• [35.]Sova, M., Saso, L., Design and development of Nrf2 modulators for cancer chemoprevention and therapy: A review, Drug Des Devel Ther, 12, (2018), 3181– 97.
• [36.]Taguchi, K., Motohashi, H., Yamamoto, M., Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution, Genes to Cells, 16(2), (2011), 123–40.
• [37.]Liu, P., Tian, W., Tao, S., Tillotson, J., Wijeratne, E.M.K., et al., Non-covalent NRF2 Activation Confers Greater Cellular Protection than Covalent Activation, Cell Chem Biol, 26(10), (2019), 1427–35.
• [38.]Samudio, I., Konopleva, M., Jr, N.H., Shi, Y.-X., McQueen, T., et al., 2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) directly targets mitochondrial glutathione to induce apoptosis in pancreatic cancer, J Biol Chem, 280(43), (2005), 36273–82.
• [39.]Robledinos-Antón, N., Fernández-Ginés, R., Manda, G., Cuadrado, A., Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development, Oxid Med Cell Longev, 2019, (2019), 9372182.
• [40.]Jain, A.D., Potteti, H., Richardson, B.G., Kingsley, L., Luciano, J.P., et al., Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators, Eur J Med Chem, 103, (2015), 252–68.
• [41.]Kang, E.S., Woo, I.S., Kim, H.J., Eun, S.Y., Paek, K.S., et al., Up-regulation of aldose reductase expression mediated by phosphatidylinositol 3-kinase/Akt and Nrf2 is involved in the protective effect of curcumin against oxidative damage, Free Radic Biol Med, 43(4), (2007), 535–45.
• [42.]Talebi, M., Talebi, M., Farkhondeh, T., New insights into the role of the Nrf2 signaling pathway in green tea catechin applications, Phyther Res, 35(6), (2021), 3078–112.
• [43.]Houghton, C.A., Fassett, R.G., Coombes, J.S., Sulforaphane and Other Nutrigenomic Nrf2 Activators : Can the Clinician’s Expectation Be Matched by the Reality?, Oxid Med Cell Longev, 2016, (2016), 7857186.
• [44.]Zhang, J., Xu, H.-X., Zhu, J.-Q., Dou, Y.-X., Xian, Y.-F., et al., Natural Nrf2 Inhibitors: A Review of Their Potential for Cancer Treatment, Int J Biol Sci, 19(10), (2023), 3029–41.
• [45.]Ren, D., Villeneuve, N.F., Jiang, T., Wu, T., Lau, A., et al., Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism, Proc Natl Acad Sci USA, 108(4), (2011), 1433–8.
• [46.]Tsuchida, K., Tsujita, T., Ojima, A., Keleku-lukwete, N., Katsuoka, F., et al., Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation, Free Radic Biol Med, 103, (2017), 236–47.
• [47.]Lu, Y., Sun, Y., Zhu, J., Yu, L., Jiang, X., et al., Oridonin exerts anticancer effect on osteosarcoma by activating PPAR- γ and inhibiting Nrf2 pathway, Cell Death Dis, 9(1), (2018), 1–16.
• [48.]Pan, S.T., Qin, Y., Zhou, Z.W., He, Z.X., Zhang, X., et al., Plumbagin suppresses epithelial to mesenchymal transition and stemness via inhibiting Nrf2-mediated signaling pathway in human tongue squamous cell carcinoma cells, Drug Des Devel Ther, 9, (2015), 5511–51.
• [49.]Arlt, A., Sebens, S., Krebs, S., Geismann, C., Grossmann, M., et al., Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity, Oncogene, 32, (2013), 4825–4835.
• [50.]Wang, X.J., Hayes, J.D., Henderson, C.J., Wolf, C.R., Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha, Proc Natl Acad Sci, 104, (2007), 19589–19594.