Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Dysregulation of NRF2 in Cancer: from Molecular Mechanisms to Therapeutic Opportunities

  • Received : 2017.09.27
  • Accepted : 2017.10.24
  • Published : 2018.01.01
Download PDF
⟨ Previous Next ⟩

Abstract

Nuclear factor E2-related factor 2 (NRF2) plays an important role in redox metabolism and antioxidant defense. Under normal conditions, NRF2 proteins are maintained at very low levels because of their ubiquitination and proteasomal degradation via binding to the kelch-like ECH associated protein 1 (KEAP1)-E3 ubiquitin ligase complex. However, oxidative and/or electrophilic stresses disrupt the KEAP1-NRF2 interaction, which leads to the accumulation and transactivation of NRF2. During recent decades, a growing body of evidence suggests that NRF2 is frequently activated in many types of cancer by multiple mechanisms, including the genetic mutations in the KEAP1-NRF2 pathway. This suggested that NRF2 inhibition is a promising strategy for cancer therapy. Recently, several NRF2 inhibitors have been reported with anti-tumor efficacy. Here, we review the mechanisms whereby NRF2 is dysregulated in cancer and its contribution to the tumor development and radiochemoresistance. In addition, among the NRF2 inhibitors reported so far, we summarize and discuss repurposed NRF2 inhibitors with their potential mechanisms and provide new insights to develop selective NRF2 inhibitors.

Keywords

References

  1. Adam, J., Hatipoglu, E., O'Flaherty, L., Ternette, N., Sahgal, N., Lockstone, H., Baban, D., Nye, E., Stamp, G. W., Wolhuter, K., Stevens, M., Fischer, R., Carmeliet, P., Maxwell, P. H., Pugh, C. W., Frizzell, N., Soga, T., Kessler, B. M., El-Bahrawy, M., Ratcliffe, P. J. and Pollard, P. J. (2011) Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20, 524-537. https://doi.org/10.1016/j.ccr.2011.09.006
  2. Ahren, B. (2008) Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes. Expert Opin. Emerg. Drugs 13, 593-607. https://doi.org/10.1517/14728210802584126
  3. Alam, M. M., Okazaki, K., Nguyen, L. T. T., Ota, N., Kitamura, H., Murakami, S., Shima, H., Igarashi, K., Sekine, H. and Motohashi, H. (2017) Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2. J. Biol. Chem. 292, 7519-7530. https://doi.org/10.1074/jbc.M116.773960
  4. Bollong, M. J., Yun, H., Sherwood, L., Woods, A. K., Lairson, L. L. and Schultz, P. G. (2015) A small molecule inhibits deregulated NRF2 transcriptional activity in cancer. ACS Chem. Biol. 10, 2193-2198. https://doi.org/10.1021/acschembio.5b00448
  5. Camp, N. D., James, R. G., Dawson, D. W., Yan, F., Davison, J. M., Houck, S. A., Tang, X., Zheng, N., Major, M. B. and Moon, R. T. (2012) Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein. J. Biol. Chem. 287, 6539-6550. https://doi.org/10.1074/jbc.M111.316471
  6. Cancer Genome Atlas Research Network (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519-525. https://doi.org/10.1038/nature11404
  7. Cancer Genome Atlas Research Network (2014) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543-550. https://doi.org/10.1038/nature13385
  8. Chae, Y. K., Arya, A., Malecek, M. K., Shin, D. S., Carneiro, B., Chandra, S., Kaplan, J., Kalyan, A., Altman, J. K., Platanias, L. and Giles, F. (2016) Repurposing metformin for cancer treatment: current clinical studies. Oncotarget 7, 40767-40780.
  9. Chen, Q., Espey, M. G., Krishna, M. C., Mitchell, J. B., Corpe, C. P., Buettner, G. R., Shacter, E. and Levine, M. (2005) Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc. Natl. Acad. Sci. U.S.A. 102, 13604-13609.
  10. Chen, W., Sun, Z., Wang, X. J., Jiang, T., Huang, Z., Fang, D. and Zhang, D. D. (2009) Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response. Mol. Cell 34, 663-673. https://doi.org/10.1016/j.molcel.2009.04.029
  11. Chen, Y., Xue, P., Hou, Y., Zhang, H., Zheng, H., Zhou, T., Qu, W., Teng, W., Zhang, Q., Andersen, M.E. and Pi, J. (2013) Isoniazid suppresses antioxidant response element activities and impairs adipogenesis in mouse and human preadipocytes. Toxicol. Appl. Pharmacol. 273, 435-441.
  12. Choi, B.-h. and Kwak, M.-K. (2016) Shadows of NRF2 in cancer: resistance to chemotherapy. Curr. Opin. Toxicol. 1, 20-28. https://doi.org/10.1016/j.cotox.2016.08.003
  13. Choi, E. J., Jung, B. J., Lee, S. H., Yoo, H. S., Shin, E. A., Ko, H. J., Chang, S., Kim, S. Y. and Jeon, S. M. (2017) A clinical drug library screen identifies clo${\beta}$sol propionate as an NRF2 inhibitor with potential therapeutic efficacy in KEAP1 mutant lung cancer. Oncogene 36, 5285-5295.
  14. Chowdhry, S., Zhang, Y., McMahon, M., Sutherland, C., Cuadrado, A. and Hayes, J. D. (2013) Nrf2 is controlled by two distinct ${\beta}$-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene 32, 3765-3781. https://doi.org/10.1038/onc.2012.388
  15. Cleary, S. P., Jeck, W. R., Zhao, X., Chen, K., Selitsky, S. R., Savich, G. L., Tan, T.-X., Wu, M. C., Getz, G., Lawrence, M. S., Parker, J. S., Li, J., Powers, S., Kim, H., Fischer, S., Guindi, M., Ghanekar, A. and Chiang, D. Y. (2013) Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology 58, 1693-1702. https://doi.org/10.1002/hep.26540
  16. Connolly, R. M., Nguyen, N. K. and Sukumar, S. (2013) Molecular pathways: current role and future directions of the retinoic acid pathway in cancer prevention and treatment. Clin. Cancer Res. 19, 1651-1659. https://doi.org/10.1158/1078-0432.CCR-12-3175
  17. Copple, I. M., Lister, A., Obeng, A. D., Kitteringham, N. R., Jenkins, R. E., Layfield, R., Foster, B. J., Goldring, C. E. and Park, B. K. (2010) Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway. J. Biol. Chem. 285, 16782-16788. https://doi.org/10.1074/jbc.M109.096545
  18. Cullinan, S. B. and Diehl, J. A. (2004) PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J. Biol. Chem. 279, 20108-20117.
  19. Cullinan, S. B., Zhang, D., Hannink, M., Arvisais, E., Kaufman, R. J. and Diehl, J. A. (2003) Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol. Cell. Biol. 23, 7198-7209.
  20. Decensi, A., Puntoni, M., Goodwin, P., Cazzaniga, M., Gennari, A., Bonanni, B. and Gandini, S. (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev. Res. (Phila.) 3, 1451-1461. https://doi.org/10.1158/1940-6207.CAPR-10-0157
  21. DeNicola, G. M., Karreth, F. A., Humpton, T. J., Gopinathan, A., Wei, C., Frese, K., Mangal, D., Yu, K. H., Yeo, C. J., Calhoun, E. S., Scrimieri, F., Winter, J. M., Hruban, R. H., Iacobuzio-Donahue, C., Kern, S. E., Blair, I. A. and Tuveson, D. A. (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106-109. https://doi.org/10.1038/nature10189
  22. Ding, B., Parmigiani, A., Divakaruni, A. S., Archer, K., Murphy, A. N. and Budanov, A. V. (2016) Sestrin2 is induced by glucose starvation via the unfolded protein response and protects cells from noncanonical necroptotic cell death. Sci. Rep. 6, 22538.
  23. Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M. and Talalay, P. (2002) Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc. Natl. Acad. Sci. U.S.A. 99, 11908-11913. https://doi.org/10.1073/pnas.172398899
  24. Do, M. T., Kim, H. G., Choi, J. H. and Jeong, H. G. (2014) Metformin induces microRNA-34a to downregulate the Sirt1/Pgc-$1{\alpha}$/Nrf2 pathway, leading to increased susceptibility of wild-type p53 cancer cells to oxidative stress and therapeutic agents. Free Radic. Biol. Med. 74, 21-34. https://doi.org/10.1016/j.freeradbiomed.2014.06.010
  25. Do, M. T., Kim, H. G., Khanal, T., Choi, J. H., Kim, D. H., Jeong, T. C. and Jeong, H. G. (2013) Metformin inhibits heme oxygenase-1 expression in cancer cells through inactivation of Raf-ERK-Nrf2 signaling and AMPK-independent pathways. Toxicol. Appl. Pharmacol. 271, 229-238. https://doi.org/10.1016/j.taap.2013.05.010
  26. Drucker, D. J. (2007) Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care 30, 1335-1343. https://doi.org/10.2337/dc07-0228
  27. Du, J., Cullen, J. J. and Buettner, G.R. (2012) Ascorbic acid: Chemistry, biology and the treatment of cancer. Biochim. Biophys. Acta 1826, 443-457.
  28. Duong, V. and Rochette-Egly, C. (2011) The molecular physiology of nuclear retinoic acid receptors. From health to disease. Biochim. Biophys. Acta 1812, 1023-1031. https://doi.org/10.1016/j.bbadis.2010.10.007
  29. Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R. and Morris, A. D. (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330, 1304-1305. https://doi.org/10.1136/bmj.38415.708634.F7
  30. Fujimoto, A., Furuta, M., Totoki, Y., Tsunoda, T., Kato, M., Shiraishi, Y., Tanaka, H., Taniguchi, H., Kawakami, Y., Ueno, M., Gotoh, K., Ariizumi, S., Wardell, C. P., Hayami, S., Nakamura, T., Aikata, H., Arihiro, K., Boroevich, K. A., Abe, T., Nakano, K., Maejima, K., Sasaki-Oku, A., Ohsawa, A., Shibuya, T., Nakamura, H., Hama, N., Hosoda, F., Arai, Y., Ohashi, S., Urushidate, T., Nagae, G., Yamamoto, S., Ueda, H., Tatsuno, K., Ojima, H., Hiraoka, N., Okusaka, T., Kubo, M., Marubashi, S., Yamada, T., Hirano, S., Yamamoto, M., Ohdan, H., Shimada, K., Ishikawa, O., Yamaue, H., Chayama, K., Miyano, S., Aburatani, H., Shibata, T. and Nakagawa, H. (2016) Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat. Genet. 48, 500-509. https://doi.org/10.1038/ng.3547
  31. Furukawa, M. and Xiong, Y. (2005) BTB Protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the cullin 3-Roc1 ligase. Mol. Cell. Biol. 25, 162-171. https://doi.org/10.1128/MCB.25.1.162-171.2005
  32. Giovannucci, E., Harlan, D. M., Archer, M. C., Bergenstal, R. M., Gapstur, S. M., Habel, L. A., Pollak, M., Regensteiner, J. G. and Yee, D. (2010) Diabetes and cancer: a consensus report. Diabetes Care 33, 1674-1685. https://doi.org/10.2337/dc10-0666
  33. Goldstein, L. D., Lee, J., Gnad, F., Klijn, C., Schaub, A., Reeder, J., Daemen, A., Bakalarski, C. E., Holcomb, T., Shames, D. S., Hartmaier, R. J., Chmielecki, J., Seshagiri, S., Gentleman, R. and Stokoe, D. (2016) Recurrent Loss of NFE2L2 Exon 2 Is a Mechanism for Nrf2 Pathway Activation in Human Cancers. Cell Rep. 16, 2605-2617. https://doi.org/10.1016/j.celrep.2016.08.010
  34. Gorrini, C., Baniasadi, P. S., Harris, I. S., Silvester, J., Inoue, S., Snow, B., Joshi, P. A., Wakeham, A., Molyneux, S. D., Martin, B., Bouwman, P., Cescon, D. W., Elia, A. J., Winterton-Perks, Z., Cruickshank, J., Brenner, D., Tseng, A., Musgrave, M., Berman, H. K., Khokha, R., Jonkers, J., Mak, T. W. and Gauthier, M. L. (2013) BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. J. Exp. Med. 210, 1529-1544. https://doi.org/10.1084/jem.20121337
  35. Guichard, C., Amaddeo, G., Imbeaud, S., Ladeiro, Y., Pelletier, L., Maad, I. B., Calderaro, J., Bioulac-Sage, P., Letexier, M., Degos, F., Clément, B., Balabaud, C., Chevet, E., Laurent, A., Couchy, G., Letouzé, E., Calvo, F. and Zucman-Rossi, J. (2012) Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat. Genet. 44, 694-698. https://doi.org/10.1038/ng.2256
  36. Hanada, N., Takahata, T., Zhou, Q., Ye, X., Sun, R., Itoh, J., Ishiguro, A., Kijima, H., Mimura, J., Itoh, K., Fukuda, S. and Saijo, Y. (2012) Methylation of the KEAP1 gene promoter region in human colorectal cancer. BMC Cancer 12, 66. https://doi.org/10.1186/1471-2407-12-66
  37. Hast, B. E., Goldfarb, D., Mulvaney, K. M., Hast, M. A., Siesser, P. F., Yan, F., Hayes, D. N. and Major, M. B. (2013) Proteomic analysis of ubiquitin ligase KEAP1 reveals associated proteins that inhibit NRF2 ubiquitination. Cancer Res. 73, 2199-2210. https://doi.org/10.1158/0008-5472.CAN-12-4400
  38. Hayes, J. D. and Dinkova-Kostova, A. T. (2014) The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 39, 199-218. https://doi.org/10.1016/j.tibs.2014.02.002
  39. Ryoo, I. G., Kim, G., Choi, B. H., Lee, S. H. and Kwak, M. K. (2016) Involvement of NRF2 signaling in doxorubicin resistance of cancer stem cell-enriched colonospheres. Biomol. Ther. (Seoul) 24, 482-488. https://doi.org/10.4062/biomolther.2016.145
  40. Inami, Y., Waguri, S., Sakamoto, A., Kouno, T., Nakada, K., Hino, O., Watanabe, S., Ando, J., Iwadate, M., Yamamoto, M., Lee, M. S., Tanaka, K. and Komatsu, M. (2011) Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J. Cell Biol. 193, 275-284. https://doi.org/10.1083/jcb.201102031
  41. Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., Yamamoto, M. and Nabeshima, Y. (1997) An Nrf2/small maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236, 313-322. https://doi.org/10.1006/bbrc.1997.6943
  42. Itoh, K., Mimura, J. and Yamamoto, M. (2010) Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Antioxid. Redox Signal. 13, 1665-1678. https://doi.org/10.1089/ars.2010.3222
  43. Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D. and Yamamoto, M. (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13, 76-86. https://doi.org/10.1101/gad.13.1.76
  44. Jain, A., Lamark, T., Sjottem, E., Bowitz Larsen, K., Atesoh Awuh, J., Overvatn, A., McMahon, M., Hayes, J.D. and Johansen, T. (2010) p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J. Biol. Chem. 285, 22576-22591. https://doi.org/10.1074/jbc.M110.118976
  45. Jeon, S.-M. (2016) Regulation and function of AMPK in physiology and diseases. Exp. Mol. Med. 48, e245. https://doi.org/10.1038/emm.2016.81
  46. Jeon, S.-M. and Hay, N. (2015) The double-edged sword of AMPK signaling in cancer and its therapeutic implications. Arch. Pharm. Res. 38, 346-357. https://doi.org/10.1007/s12272-015-0549-z
  47. Jeon, S. M. and Hay, N. (2012) The dark face of AMPK as an essential tumor promoter. Cell Logist 2, 197-202. https://doi.org/10.4161/cl.22651
  48. Jia, Y., Wang, H., Wang, Q., Ding, H., Wu, H. and Pan, H. (2016) Silencing Nrf2 impairs glioma cell proliferation via AMPK-activated mTOR inhibition. Biochem. Biophys. Res. Commun. 469, 665-671. https://doi.org/10.1016/j.bbrc.2015.12.034
  49. Jiang, T., Chen, N., Zhao, F., Wang, X. J., Kong, B., Zheng, W. and Zhang, D. D. (2010) High levels of Nrf2 determine chemoresistance in type II endometrial cancer. Cancer Res. 70, 5486-5496. https://doi.org/10.1158/0008-5472.CAN-10-0713
  50. Joo, M. S., Kim, W. D., Lee, K. Y., Kim, J. H., Koo, J. H. and Kim, S. G. (2016) AMPK facilitates nuclear accumulation of Nrf2 by phosphorylating at serine 550. Mol. Cell. Biol. 36, 1931-1942. https://doi.org/10.1128/MCB.00118-16
  51. Kadmiel, M. and Cidlowski, J. A. (2013) Glucocorticoid receptor signaling in health and disease. Trends Pharmacol. Sci. 34, 518-530. https://doi.org/10.1016/j.tips.2013.07.003
  52. Kassel, O. and Herrlich, P. (2007) Crosstalk between the glucocorticoid receptor and other transcription factors: molecular aspects. Mol. Cell. Endocrinol. 275, 13-29.
  53. Kasznicki, J., Sliwinska, A. and Drzewoski, J. (2014) Metformin in cancer prevention and therapy. Ann. Transl. Med. 2, 57.
  54. Katoh, Y., Iida, K., Kang, M.-I., Kobayashi, A., Mizukami, M., Tong, K. I., McMahon, M., Hayes, J. D., Itoh, K. and Yamamoto, M. (2005) Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome. Arch. Biochem. Biophys. 433, 342-350. https://doi.org/10.1016/j.abb.2004.10.012
  55. Katoh, Y., Itoh, K., Yoshida, E., Miyagishi, M., Fukamizu, A. and Yamamoto, M. (2001) Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 6, 857-868. https://doi.org/10.1046/j.1365-2443.2001.00469.x
  56. Ki, S. H., Cho, I. J., Choi, D. W. and Kim, S. G. (2005) Glucocorticoid receptor (GR)-associated SMRT binding to $C/EBP{\beta}$ TAD and Nrf2 Neh4/5: role of SMRT recruited to GR in GSTA2 gene repression. Mol. Cell. Biol. 25, 4150-4165. https://doi.org/10.1128/MCB.25.10.4150-4165.2005
  57. Kim, Y. R., Oh, J. E., Kim, M. S., Kang, M. R., Park, S. W., Han, J. Y., Eom, H. S., Yoo, N. J. and Lee, S. H. (2010) Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J. Pathol. 220, 446-451. https://doi.org/10.1002/path.2653
  58. Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y.-S., Ueno, I., Sakamoto, A., Tong, K.I., Kim, M., Nishito, Y., Iemura, S., Natsume, T., Ueno, T., Kominami, E., Motohashi, H., Tanaka, K. and Yamamoto, M. (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 12, 213-223. https://doi.org/10.1038/ncb2021
  59. Konstantinopoulos, P. A., Spentzos, D., Fountzilas, E., Francoeur, N., Sanisetty, S., Grammatikos, A. P., Hecht, J. L. and Cannistra, S. A. (2011) Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer. Cancer Res. 71, 5081-5089. https://doi.org/10.1158/0008-5472.CAN-10-4668
  60. Koumenis, C., Hammond, E. and Giaccia, A. (2014) Tumor microenvironment and cellular stress: signaling, metabolism, imaging, and therapeutic targets. Preface. Adv. Exp. Med. Biol. 772, v-viii.
  61. Kratschmar, D. V., Calabrese, D., Walsh, J., Lister, A., Birk, J., Appenzeller-Herzog, C., Moulin, P., Goldring, C. E. and Odermatt, A. (2012) Suppression of the Nrf2-dependent antioxidant response by glucocorticoids and $11{\beta}$-HSD1-mediated glucocorticoid activation in hepatic cells. PLoS ONE 7, e36774. https://doi.org/10.1371/journal.pone.0036774
  62. Kwak, M.-K. and Kensler, T. W. (2010) Targeting NRF2 signaling for cancer chemoprevention. Toxicol. Appl. Pharmacol. 244, 66-76. https://doi.org/10.1016/j.taap.2009.08.028
  63. Lau, A., Wang, X.-J., Zhao, F., Villeneuve, N. F., Wu, T., Jiang, T., Sun, Z., White, E. and Zhang, D. D. (2010) A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol. Cell. Biol. 30, 3275-3285. https://doi.org/10.1128/MCB.00248-10
  64. Leinonen, H. M., Kansanen, E., Polonen, P., Heinaniemi, M. and Levonen, A. L. (2015) Dysregulation of the Keap1-Nrf2 pathway in cancer. Biochem. Soc. Trans. 43, 645-649. https://doi.org/10.1042/BST20150048
  65. Li, W., Yu, S. W. and Kong, A. N. (2006) Nrf2 possesses a redox-sensitive nuclear exporting signal in the Neh5 transactivation domain. J. Biol. Chem. 281, 27251-27263. https://doi.org/10.1074/jbc.M602746200
  66. Liao, H., Zhou, Q., Zhang, Z., Wang, Q., Sun, Y., Yi, X. and Feng, Y. (2012) NRF2 is overexpressed in ovarian epithelial carcinoma and is regulated by gonadotrophin and sex-steroid hormones. Oncol. Rep. 27, 1918-1924.
  67. Liu, Q., Ci, X., Wen, Z. and Peng, L. (2017) Diosmetin alleviates lipopolysaccharide- induced acute lung injury through activating the Nrf2 pathway and inhibiting the NLRP3 inflammasome. Biomol. Ther. (Seoul) doi: 10.4062/biomolther.2016.234 [Epub ahead of print].
  68. Lu, K., Alcivar, A. L., Ma, J., Foo, T. K., Zywea, S., Mahdi, A., Huo, Y., Kensler, T. W., Gatza, M. L. and Xia, B. (2017) NRF2 induction supporting breast cancer cell survival is enabled by oxidative stressinduced DPP3-KEAP1 interaction. Cancer Res. 77, 2881-2892.
  69. Ma, J., Cai, H., Wu, T., Sobhian, B., Huo, Y., Alcivar, A., Mehta, M., Cheung, K. L., Ganesan, S., Kong, A. N., Zhang, D. D. and Xia, B. (2012) PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function. Mol. Cell. Biol. 32, 1506-1517. https://doi.org/10.1128/MCB.06271-11
  70. Mandl, J., Szarka, A. and Bánhegyi, G. (2009) Vitamin C: update on physiology and pharmacology. Br. J. Pharmacol. 157, 1097-1110.
  71. Martinez, V. D., Vucic, E. A., Thu, K. L., Pikor, L. A., Hubaux, R. and Lam, W. L. (2014) Unique pattern of component gene disruption in the NRF2 inhibitor KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex in serous ovarian cancer. Biomed. Res. Int. 2014, 159459.
  72. Menegon, S., Columbano, A. and Giordano, S. (2016) The dual roles of NRF2 in cancer. Trends Mol. Med. 22, 578-593. https://doi.org/10.1016/j.molmed.2016.05.002
  73. Mitsuishi, Y., Taguchi, K., Kawatani, Y., Shibata, T., Nukiwa, T., Aburatani, H., Yamamoto, M. and Motohashi, H. (2012) Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66-79. https://doi.org/10.1016/j.ccr.2012.05.016
  74. Moi, P., Chan, K., Asunis, I., Cao, A. and Kan, Y. W. (1994) Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the ${\beta}$-globin locus control region. Proc. Natl. Acad. Sci. U.S.A. 91, 9926-9930. https://doi.org/10.1073/pnas.91.21.9926
  75. Morales, D. R. and Morris, A. D. (2015) Metformin in cancer treatment and prevention. Annu. Rev. Med. 66, 17-29.
  76. Muscarella, L. A., Parrella, P., D'Alessandro, V., la Torre, A., Barbano, R., Fontana, A., Tancredi, A., Guarnieri, V., Balsamo, T., Coco, M., Copetti, M., Pellegrini, F., De Bonis, P., Bisceglia, M., Scaramuzzi, G., Maiello, E., Valori, V. M., Merla, G., Vendemiale, G. and Fazio, V. M. (2011) Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer. Epigenetics 6, 710-719. https://doi.org/10.4161/epi.6.6.15773
  77. Nioi, P. and Nguyen, T. (2007) A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity. Biochem. Biophys. Res. Commun. 362, 816-821. https://doi.org/10.1016/j.bbrc.2007.08.051
  78. Nioi, P., Nguyen, T., Sherratt, P. J. and Pickett, C. B. (2005) The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol. Cell. Biol. 25, 10895-10906. https://doi.org/10.1128/MCB.25.24.10895-10906.2005
  79. No, J. H., Kim, Y. B. and Song, Y. S. (2014) Targeting nrf2 signaling to combat chemoresistance. J. Cancer Prev. 19, 111-117. https://doi.org/10.15430/JCP.2014.19.2.111
  80. Noh, Y., Kang, D. R., Kim, D. J., Lee, K. J., Lee, S. and Shin, S. (2017) Impact of clinical evidence communications and drug regulation changes concerning rosiglitazone on prescribing patterns of antidiabetic therapies. Pharmacoepidemiol. Drug Saf. 26, 1338-1346. https://doi.org/10.1002/pds.4262
  81. Ohta, T., Iijima, K., Miyamoto, M., Nakahara, I., Tanaka, H., Ohtsuji, M., Suzuki, T., Kobayashi, A., Yokota, J., Sakiyama, T., Shibata, T., Yamamoto, M. and Hirohashi, S. (2008) Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res. 68, 1303-1309. https://doi.org/10.1158/0008-5472.CAN-07-5003
  82. Ooi, A., Dykema, K., Ansari, A., Petillo, D., Snider, J., Kahnoski, R., Anema, J., Craig, D., Carpten, J., Teh, B. T. and Furge, K. A. (2013) CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma. Cancer Res. 73, 2044-2051. https://doi.org/10.1158/0008-5472.CAN-12-3227
  83. Ooi, A., Wong, J. C., Petillo, D., Roossien, D., Perrier-Trudova, V., Whitten, D., Min, B. W., Tan, M. H., Zhang, Z., Yang, X. J., Zhou, M., Gardie, B., Molinié, V., Richard, S., Tan, P. H., Teh, B. T. and Furge, K. A. (2011) An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20, 511-523. https://doi.org/10.1016/j.ccr.2011.08.024
  84. Peng, H., Wang, H., Xue, P., Hou, Y., Dong, J., Zhou, T., Qu, W., Peng, S., Li, J., Carmichael, P. L., Nelson, B., Clewell, R., Zhang, Q., Andersen, M. E. and Pi, J. (2016) Suppression of NRF2-ARE activity sensitizes chemotherapeutic agent-induced cytotoxicity in human acute monocytic leukemia cells. Toxicol. Appl. Pharmacol. 292, 1-7. https://doi.org/10.1016/j.taap.2015.12.008
  85. Phung, O. J., Scholle, J. M., Talwar, M. and Coleman, C. I. (2010) Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA 303, 1410-1418. https://doi.org/10.1001/jama.2010.405
  86. Rada, P., Rojo, A. I., Chowdhry, S., McMahon, M., Hayes, J. D. and Cuadrado, A. (2011) $SCF/{\beta}$-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol. Cell. Biol. 31, 1121-1133. https://doi.org/10.1128/MCB.01204-10
  87. Ramappa, V. and Aithal, G. P. (2013) Hepatotoxicity related to antituberculosis drugs: mechanisms and management. J. Clin. Exp. Hepatol. 3, 37-49. https://doi.org/10.1016/j.jceh.2012.12.001
  88. Ramos-Gomez, M., Kwak, M.-K., Dolan, P. M., Itoh, K., Yamamoto, M., Talalay, P. and Kensler, T. W. (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc. Natl. Acad. Sci. U.S.A. 98, 3410-3415.
  89. Ranzato, E., Biffo, S. and Burlando, B. (2011) Selective ascorbate toxicity in malignant mesothelioma: a redox Trojan mechanism. Am. J. Respir. Cell Mol. Biol. 44, 108-117. https://doi.org/10.1165/rcmb.2009-0340OC
  90. Rojas, L. B. A. and Gomes, M. B. (2013) Metformin: an old but still the best treatment for type 2 diabetes. Diabetol. Metab. Syndr. 5, 6.
  91. Rushworth, S. A., MacEwan, D. J. and O'Connell, M. A. (2008) Lipopolysaccharide- induced expression of NAD(P)H:quinone oxidoreductase 1 and heme oxygenase-1 protects against excessive inflammatory responses in human monocytes. J. Immunol. 181, 6730-6737. https://doi.org/10.4049/jimmunol.181.10.6730
  92. Rushworth, S. A., Zaitseva, L., Murray, M. Y., Shah, N. M., Bowles, K. M. and MacEwan, D. J. (2012) The high Nrf2 expression in human acute myeloid leukemia is driven by NF-${\kappa}B$ and underlies its chemo-resistance. Blood 120, 5188-5198. https://doi.org/10.1182/blood-2012-04-422121
  93. Shi, L., Wu, L., Chen, Z., Yang, J., Chen, X., Yu, F., Zheng, F. and Lin, X. (2015) MiR-141 activates Nrf2-dependent antioxidant pathway via down-regulating the expression of Keap1 conferring the resistance of hepatocellular carcinoma cells to 5-fluorouracil. Cell. Physiol. Biochem. 35, 2333-2348. https://doi.org/10.1159/000374036
  94. Shibata, T., Kokubu, A., Gotoh, M., Ojima, H., Ohta, T., Yamamoto, M. and Hirohashi, S. (2008a) Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterology 135, 1358-1368.e4. https://doi.org/10.1053/j.gastro.2008.06.082
  95. Shibata, T., Kokubu, A., Saito, S., Narisawa-Saito, M., Sasaki, H., Aoyagi, K., Yoshimatsu, Y., Tachimori, Y., Kushima, R., Kiyono, T. and Yamamoto, M. (2011) NRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancer. Neoplasia 13, 864-873.
  96. Shibata, T., Ohta, T., Tong, K. I., Kokubu, A., Odogawa, R., Tsuta, K., Asamura, H., Yamamoto, M. and Hirohashi, S. (2008b) Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc. Natl. Acad. Sci. U.S.A. 105, 13568-13573. https://doi.org/10.1073/pnas.0806268105
  97. Singh, A., Misra, V., Thimmulappa, R. K., Lee, H., Ames, S., Hoque, M. O., Herman, J. G., Baylin, S. B., Sidransky, D., Gabrielson, E., Brock, M. V. and Biswal, S. (2006) Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 3, e420.
  98. Singh, A., Venkannagari, S., Oh, K. H., Zhang, Y.-Q., Rohde, J. M., Liu, L., Nimmagadda, S., Sudini, K., Brimacombe, K. R., Gajghate, S., Ma, J., Wang, A., Xu, X., Shahane, S. A., Xia, M., Woo, J., Mensah, G. A., Wang, Z., Ferrer, M., Gabrielson, E., Li, Z., Rastinejad, F., Shen, M., Boxer, M. B. and Biswal, S. (2016) Small molecule inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors. ACS Chem. Biol. 11, 3214-3225. https://doi.org/10.1021/acschembio.6b00651
  99. Sjoblom, T., Jones, S., Wood, L. D., Parsons, D. W., Lin, J., Barber, T. D., Mandelker, D., Leary, R. J., Ptak, J., Silliman, N., Szabo, S., Buckhaults, P., Farrell, C., Meeh, P., Markowitz, S. D., Willis, J., Dawson, D., Willson, J. K., Gazdar, A. F., Hartigan, J., Wu, L., Liu, C., Parmigiani, G., Park, B. H., Bachman, K. E., Papadopoulos, N., Vogelstein, B., Kinzler, K. W. and Velculescu, V. E. (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314, 268-274. https://doi.org/10.1126/science.1133427
  100. Sporn, M. B. and Liby, K. T. (2012) NRF2 and cancer: the good, the bad and the importance of context. Nat. Rev. Cancer 12, 564-571. https://doi.org/10.1038/nrc3278
  101. Sundahl, N., Clarisse, D., Bracke, M., Offner, F., Berghe, W. V. and Beck, I. M. (2016) Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments. Oncoscience 3, 188-202.
  102. Madduma Hewage, S. R. K., Piao, M. J., Kang, K. A., Ryu, Y. S., Fernando, P. M. D. J., Oh, M. C., Park, J. E., Shilnikova, K., Moon, Y. J., Shin, D. O. and Hyun, J. W. (2017) Galangin activates the ERK/AKT-driven Nrf2 signaling pathway to increase the level of reduced glutathione in human keratinocytes. Biomol. Ther. (Seoul) 25, 427-433.
  103. Taguchi, K., Motohashi, H. and Yamamoto, M. (2011) Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells 16, 123-140. https://doi.org/10.1111/j.1365-2443.2010.01473.x
  104. Taguchi, K. and Yamamoto, M. (2017) The KEAP1-NRF2 System in Cancer. Front. Oncol. 7, 85. https://doi.org/10.3389/fonc.2017.00085
  105. Tao, S., Wang, S., Moghaddam, S. J., Ooi, A., Chapman, E., Wong, P. K. and Zhang, D. D. (2014) Oncogenic KRAS confers chemoresistance by upregulating NRF2. Cancer Res. 74, 7430-7441.
  106. Tarumoto, T., Nagai, T., Ohmine, K., Miyoshi, T., Nakamura, M., Kondo, T., Mitsugi, K., Nakano, S., Muroi, K., Komatsu, N. and Ozawa, K. (2004) Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line. Exp. Hematol. 32, 375-381. https://doi.org/10.1016/j.exphem.2004.01.007
  107. Tebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., Dinkova-Kostova, A. T. and Hayes, J. D. (2015) Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic. Biol. Med. 88, 108-146. https://doi.org/10.1016/j.freeradbiomed.2015.06.021
  108. Tong, K. I., Katoh, Y., Kusunoki, H., Itoh, K., Tanaka, T. and Yamamoto, M. (2006) Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol. Cell. Biol. 26, 2887-2900. https://doi.org/10.1128/MCB.26.8.2887-2900.2006
  109. Umemura, A., He, F., Taniguchi, K., Nakagawa, H., Yamachika, S., Font-Burgada, J., Zhong, Z., Subramaniam, S., Raghunandan, S., Duran, A., Linares, J. F., Reina-Campos, M., Umemura, S., Valasek, M. A., Seki, E., Yamaguchi, K., Koike, K., Itoh, Y., Diaz-Meco, M. T., Moscat, J. and Karin, M. (2016) p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell 29, 935-948. https://doi.org/10.1016/j.ccell.2016.04.006
  110. Valenzuela, M., Glorieux, C., Stockis, J., Sid, B., Sandoval, J. M., Felipe, K. B., Kviecinski, M. R., Verrax, J. and Buc Calderon, P. (2014) Retinoic acid synergizes ATO-mediated cytotoxicity by precluding Nrf2 activity in AML cells. Br. J. Cancer 111, 874-882. https://doi.org/10.1038/bjc.2014.380
  111. van Jaarsveld, M. T. M., Helleman, J., Boersma, A. W. M., van Kuijk, P. F., van Ijcken, W. F., Despierre, E., Vergote, I., Mathijssen, R. H. J., Berns, E. M. J. J., Verweij, J., Pothof, J. and Wiemer, E. A. (2013) miR-141 regulates KEAP1 and modulates cisplatin sensitivity in ovarian cancer cells. Oncogene 32, 4284-4293. https://doi.org/10.1038/onc.2012.433
  112. Verma, A. K., Yadav, A., Dewangan, J., Singh, S. V., Mishra, M., Singh, P. K. and Rath, S. K. (2015) Isoniazid prevents Nrf2 translocation by inhibiting ERK1 phosphorylation and induces oxidative stress and apoptosis. Redox. Biol. 6, 80-92. https://doi.org/10.1016/j.redox.2015.06.020
  113. Vilcheze, C. and Jacobs, W. R., Jr. (2014) Resistance to isoniazid and ethionamide in mycobacterium tuberculosis: genes, mutations, and causalities. Microbiol. Spectr. 2, MGM2-0014-2013.
  114. Wagner, A. E., Boesch-Saadatmandi, C., Breckwoldt, D., Schrader, C., Schmelzer, C., Doring, F., Hashida, K., Hori, O., Matsugo, S. and Rimbach, G. (2011) Ascorbic acid partly antagonizes resveratrol mediated heme oxygenase-1 but not paraoxonase-1 induction in cultured hepatocytes - role of the redox-regulated transcription factor Nrf2. BMC Complement Altern Med 11, 1. https://doi.org/10.1186/1472-6882-11-1
  115. Wang, H., Liu, K., Geng, M., Gao, P., Wu, X., Hai, Y., Li, Y., Li, Y., Luo, L., Hayes, J. D., Wang, X. J. and Tang, X. (2013) $RXR{\alpha}$ inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2. Cancer Res. 73, 3097-3108. https://doi.org/10.1158/0008-5472.CAN-12-3386
  116. Wang, H., Liu, X., Long, M., Huang, Y., Zhang, L., Zhang, R., Zheng, Y., Liao, X., Wang, Y., Liao, Q., Li, W., Tang, Z., Tong, Q., Wang, X., Fang, F., Rojo de la Vega, M., Ouyang, Q., Zhang, D. D., Yu, S., Zheng, H. (2016) NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis. Sci. Transl. Med. 8, 334ra51. https://doi.org/10.1126/scitranslmed.aad6095
  117. Wang, Q., Ma, J., Lu, Y., Zhang, S., Huang, J., Chen, J., Bei, J.X., Yang, K., Wu, G., Huang, K., Chen, J. and Xu, S. (2017) CDK20 interacts with KEAP1 to activate NRF2 and promotes radiochemoresistance in lung cancer cells. Oncogene 36, 5321-5330. https://doi.org/10.1038/onc.2017.161
  118. Wang, R., An, J., Ji, F., Jiao, H., Sun, H. and Zhou, D. (2008) Hypermethylation of the Keap1 gene in human lung cancer cell lines and lung cancer tissues. Biochem. Biophys. Res. Commun. 373, 151-154. https://doi.org/10.1016/j.bbrc.2008.06.004
  119. Wang, X. J., Hayes, J. D., Henderson, C. J. and Wolf, C. R. (2007) Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor ${\alpha}$. Proc. Natl. Acad. Sci. U.S.A. 104, 19589-19594. https://doi.org/10.1073/pnas.0709483104
  120. Yamamoto, S., Inoue, J., Kawano, T., Kozaki, K.-i., Omura, K. and Inazawa, J. (2014) The Impact of miRNA-Based Molecular Diagnostics and Treatment of NRF2-Stabilized Tumors. Mol. Cancer Res. 12, 58-68. https://doi.org/10.1158/1541-7786.MCR-13-0246-T
  121. Yoo, N. J., Kim, H. R., Kim, Y. R., An, C. H. and Lee, S. H. (2012) Somatic mutations of the KEAP1 gene in common solid cancers. Histopathology 60, 943-952. https://doi.org/10.1111/j.1365-2559.2012.04178.x
  122. Yun, J., Mullarky, E., Lu, C., Bosch, K. N., Kavalier, A., Rivera, K., Roper, J., Chio, I. I., Giannopoulou, E. G., Rago, C., Muley, A., Asara, J. M., Paik, J., Elemento, O., Chen, Z., Pappin, D. J., Dow, L. E., Papadopoulos, N., Gross, S. S. and Cantley, L. C. (2015) Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391-1396. https://doi.org/10.1126/science.aaa5004
  123. Zhang, D. D., Lo, S.-C., Cross, J. V., Templeton, D. J. and Hannink, M. (2004) Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol. Cell. Biol. 24, 10941-10953. https://doi.org/10.1128/MCB.24.24.10941-10953.2004
  124. Zhang, P., Singh, A., Yegnasubramanian, S., Esopi, D., Kombairaju, P., Bodas, M., Wu, H., Bova, S. G. and Biswal, S. (2010) Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Mol. Cancer Ther. 9, 336-346. https://doi.org/10.1158/1535-7163.MCT-09-0589
  125. Zhang, Z., Wang, Q., Ma, J., Yi, X., Zhu, Y., Xi, X., Feng, Y. and Jin, Z. (2013) Reactive oxygen species regulate FSH-induced expression of vascular endothelial growth factor via Nrf2 and $HIF1{\alpha}$ signaling in human epithelial ovarian cancer. Oncol. Rep. 29, 1429-1434. https://doi.org/10.3892/or.2013.2278
  126. Zhao, X. Q., Zhang, Y. F., Xia, Y. F., Zhou, Z. M. and Cao, Y. Q. (2015) Promoter demethylation of nuclear factor-erythroid 2-related factor 2 gene in drug-resistant colon cancer cells. Oncol. Lett. 10, 1287-1292. https://doi.org/10.3892/ol.2015.3468
  127. Zhou, S., Ye, W., Shao, Q., Zhang, M. and Liang, J. (2013) Nrf2 is a potential therapeutic target in radioresistance in human cancer. Crit. Rev. Oncol. Hematol. 88, 706-715. https://doi.org/10.1016/j.critrevonc.2013.09.001
  128. Zhu, J., Wang, H., Chen, F., Fu, J., Xu, Y., Hou, Y., Kou, H. H., Zhai, C., Nelson, M. B., Zhang, Q., Andersen, M. E. and Pi, J. (2016) An overview of chemical inhibitors of the Nrf2-ARE signaling pathway and their potential applications in cancer therapy. Free Radic. Biol. Med. 99, 544-556. https://doi.org/10.1016/j.freeradbiomed.2016.09.010
  129. Zimmermann, K., Baldinger, J., Mayerhofer, B., Atanasov, A. G., Dirsch, V. M. and Heiss, E. H. (2015) Activated AMPK boosts the Nrf2/HO-1 signaling axis-a role for the unfolded protein response. Free Radic. Biol. Med. 88, 417-426. https://doi.org/10.1016/j.freeradbiomed.2015.03.030
  130. Zipper, L. M. and Mulcahy, R. T. (2002) The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. J. Biol. Chem. 277, 36544-36552. https://doi.org/10.1074/jbc.M206530200

Cited by

  1. Cancer Metabolism: a Hope for Curing Cancer vol.26, pp.1, 2018, https://doi.org/10.4062/biomolther.2017.300
  2. Cancer-Associated Function of 2-Cys Peroxiredoxin Subtypes as a Survival Gatekeeper vol.7, pp.11, 2018, https://doi.org/10.3390/antiox7110161
  3. Therapeutic Modulation of Virus-Induced Oxidative Stress via the Nrf2-Dependent Antioxidative Pathway vol.2018, pp.1942-0994, 2018, https://doi.org/10.1155/2018/6208067
  4. New highlights on the health-improving effects of sulforaphane vol.9, pp.5, 2018, https://doi.org/10.1039/C8FO00018B
  5. Systems Biology Approach to Identify Novel Genomic Determinants for Pancreatic Cancer Pathogenesis vol.9, pp.1, 2019, https://doi.org/10.1038/s41598-018-36328-w
  6. TTB Protects Astrocytes Against Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury via Activation of Nrf2/HO-1 Signaling Pathway vol.10, pp.None, 2019, https://doi.org/10.3389/fphar.2019.00792
  7. Potential Applications of NRF2 Inhibitors in Cancer Therapy vol.2019, pp.None, 2019, https://doi.org/10.1155/2019/8592348
  8. Targeting the cell signaling pathway Keap1-Nrf2 as a therapeutic strategy for adenocarcinomas of the lung vol.23, pp.3, 2019, https://doi.org/10.1080/14728222.2019.1559824
  9. Luteolin promotes apoptotic cell death via upregulation of Nrf2 expression by DNA demethylase and the interaction of Nrf2 with p53 in human colon cancer cells vol.51, pp.4, 2019, https://doi.org/10.1038/s12276-019-0238-y
  10. Pharmacological Applications of Nrf2 Inhibitors as Potential Antineoplastic Drugs vol.20, pp.8, 2019, https://doi.org/10.3390/ijms20082025
  11. Diosmetin induces apoptosis and enhances the chemotherapeutic efficacy of paclitaxel in non‐small cell lung cancer cells via Nrf2 inhibition vol.176, pp.12, 2018, https://doi.org/10.1111/bph.14652
  12. Can Nrf2 Modulate the Development of Intestinal Fibrosis and Cancer in Inflammatory Bowel Disease? vol.20, pp.16, 2019, https://doi.org/10.3390/ijms20164061
  13. The Role of Nrf2 Activity in Cancer Development and Progression vol.11, pp.11, 2019, https://doi.org/10.3390/cancers11111755
  14. Mechanism of Emulsified Isoflurane Postconditioning-Induced Activation of the Nrf2-Antioxidant Response Element Signaling Pathway During Myocardial Ischemia-Reperfusion : The Relationship With Reactiv vol.73, pp.5, 2018, https://doi.org/10.1097/fjc.0000000000000668
  15. Isolation of strawberry anthocyanin-rich fractions and their mechanisms of action against murine breast cancer cell lines vol.10, pp.11, 2018, https://doi.org/10.1039/c9fo01721f
  16. A Potential Mechanism of Temozolomide Resistance in Glioma–Ferroptosis vol.10, pp.None, 2018, https://doi.org/10.3389/fonc.2020.00897
  17. CRISPR-Generated Nrf2a Loss- and Gain-of-Function Mutants Facilitate Mechanistic Analysis of Chemical Oxidative Stress-Mediated Toxicity in Zebrafish vol.33, pp.2, 2018, https://doi.org/10.1021/acs.chemrestox.9b00346
  18. The GTPase KRAS suppresses the p53 tumor suppressor by activating the NRF2-regulated antioxidant defense system in cancer cells vol.295, pp.10, 2018, https://doi.org/10.1074/jbc.ra119.011930
  19. NRF2-driven redox metabolism takes center stage in cancer metabolism from an outside-in perspective vol.43, pp.3, 2020, https://doi.org/10.1007/s12272-020-01224-3
  20. Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics vol.21, pp.9, 2020, https://doi.org/10.3390/ijms21093100
  21. Oxidative Stress and Cancer Development: Are Noncoding RNAs the Missing Links? vol.33, pp.17, 2018, https://doi.org/10.1089/ars.2019.7987
  22. Apoptosis Inducing Activity of Rhinacanthin-C in Doxorubicin-Resistant Breast Cancer MCF-7 Cells vol.44, pp.9, 2018, https://doi.org/10.1248/bpb.b21-00015
  23. Regulation of redox processes in biological systems with the participation of the Keap1/Nrf2/ARE signaling pathway, biogenic selenium nanoparticles as Nrf2 activators vol.11, pp.4, 2018, https://doi.org/10.15421/022074
  24. Therapeutic Targeting of the NRF2 Signaling Pathway in Cancer vol.26, pp.5, 2021, https://doi.org/10.3390/molecules26051417
  25. Recent Progress in Discovering the Role of Carotenoids and Their Metabolites in Prostatic Physiology and Pathology with a Focus on Prostate Cancer-A Review-Part I: Molecular Mechanisms of Carotenoid A vol.10, pp.4, 2021, https://doi.org/10.3390/antiox10040585
  26. Lactobacillus plantarum HFY09 alleviates alcohol‐induced gastric ulcers in mice via an anti‐oxidative mechanism vol.45, pp.5, 2021, https://doi.org/10.1111/jfbc.13726
  27. Signaling, metabolism, and cancer: An important relationship for therapeutic intervention vol.236, pp.8, 2021, https://doi.org/10.1002/jcp.30276
  28. Modulation of Nrf2 and NF-κB Signaling Pathways by Naturally Occurring Compounds in Relation to Cancer Prevention and Therapy. Are Combinations Better Than Single Compounds? vol.22, pp.15, 2021, https://doi.org/10.3390/ijms22158223
  29. Synthetic Retinoids as Potential Therapeutics in Prostate Cancer-An Update of the Last Decade of Research: A Review vol.22, pp.19, 2018, https://doi.org/10.3390/ijms221910537
  30. Attenuation of Pancreatic Cancer In Vitro and In Vivo via Modulation of Nrf2 and NF-κB Signaling Pathways by Natural Compounds vol.10, pp.12, 2018, https://doi.org/10.3390/cells10123556
  31. Nrf2/Keap1/ARE signaling: Towards specific regulation vol.291, pp.None, 2022, https://doi.org/10.1016/j.lfs.2021.120111