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http://dx.doi.org/10.4062/biomolther.2017.195

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

Jung, Byung-Jin (College of Pharmacy, Ajou University)
Yoo, Hwan-Sic (College of Pharmacy, Ajou University)
Shin, Sooyoung (College of Pharmacy, Ajou University)
Park, Young-Joon (College of Pharmacy, Ajou University)
Jeon, Sang-Min (College of Pharmacy, Ajou University)
Publication Information
Biomolecules & Therapeutics / v.26, no.1, 2018 , pp. 57-68 More about this Journal
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
NRF2; KEAP1; NRF2 inhibitors; Cancer;
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1 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.   DOI
2 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.   DOI
3 Cancer Genome Atlas Research Network (2014) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543-550.   DOI
4 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.
5 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.
6 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.   DOI
7 Ahren, B. (2008) Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes. Expert Opin. Emerg. Drugs 13, 593-607.   DOI
8 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.   DOI
9 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.
10 Cancer Genome Atlas Research Network (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519-525.   DOI
11 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.
12 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.   DOI
13 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.   DOI
14 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.
15 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.   DOI
16 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.   DOI
17 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.   DOI
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 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.   DOI
20 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.   DOI
21 Choi, B.-h. and Kwak, M.-K. (2016) Shadows of NRF2 in cancer: resistance to chemotherapy. Curr. Opin. Toxicol. 1, 20-28.   DOI
22 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.
23 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.   DOI
24 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.   DOI
25 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.   DOI
26 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.
27 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.   DOI
28 Taguchi, K. and Yamamoto, M. (2017) The KEAP1-NRF2 System in Cancer. Front. Oncol. 7, 85.   DOI
29 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.   DOI
30 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.   DOI
31 Morales, D. R. and Morris, A. D. (2015) Metformin in cancer treatment and prevention. Annu. Rev. Med. 66, 17-29.
32 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.   DOI
33 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.   DOI
34 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.   DOI
35 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.
36 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.   DOI
37 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.   DOI
38 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.   DOI
39 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.
40 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.   DOI
41 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.   DOI
42 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.   DOI
43 No, J. H., Kim, Y. B. and Song, Y. S. (2014) Targeting nrf2 signaling to combat chemoresistance. J. Cancer Prev. 19, 111-117.   DOI
44 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.   DOI
45 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.   DOI
46 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.   DOI
47 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.   DOI
48 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.   DOI
49 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.   DOI
50 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.   DOI
51 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.   DOI
52 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.   DOI
53 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.   DOI
54 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.   DOI
55 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.   DOI
56 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.   DOI
57 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.   DOI
58 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.   DOI
59 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.   DOI
60 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.
61 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.   DOI
62 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.   DOI
63 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.   DOI
64 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.   DOI
65 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.   DOI
66 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.   DOI
67 Jeon, S.-M. (2016) Regulation and function of AMPK in physiology and diseases. Exp. Mol. Med. 48, e245.   DOI
68 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.   DOI
69 Jeon, S. M. and Hay, N. (2012) The dark face of AMPK as an essential tumor promoter. Cell Logist 2, 197-202.   DOI
70 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.   DOI
71 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.   DOI
72 Ramappa, V. and Aithal, G. P. (2013) Hepatotoxicity related to antituberculosis drugs: mechanisms and management. J. Clin. Exp. Hepatol. 3, 37-49.   DOI
73 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.
74 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.   DOI
75 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.   DOI
76 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.   DOI
77 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.   DOI
78 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.   DOI
79 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.   DOI
80 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.   DOI
81 Kadmiel, M. and Cidlowski, J. A. (2013) Glucocorticoid receptor signaling in health and disease. Trends Pharmacol. Sci. 34, 518-530.   DOI
82 Kassel, O. and Herrlich, P. (2007) Crosstalk between the glucocorticoid receptor and other transcription factors: molecular aspects. Mol. Cell. Endocrinol. 275, 13-29.
83 Kasznicki, J., Sliwinska, A. and Drzewoski, J. (2014) Metformin in cancer prevention and therapy. Ann. Transl. Med. 2, 57.
84 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.   DOI
85 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.   DOI
86 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.   DOI
87 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.   DOI
88 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.   DOI
89 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.   DOI
90 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.   DOI
91 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.   DOI
92 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.   DOI
93 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.   DOI
94 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.   DOI
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 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.
97 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.   DOI
98 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.   DOI
99 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.   DOI
100 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.   DOI
101 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.   DOI
102 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.   DOI
103 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.
104 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.   DOI
105 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.   DOI
106 Mandl, J., Szarka, A. and Bánhegyi, G. (2009) Vitamin C: update on physiology and pharmacology. Br. J. Pharmacol. 157, 1097-1110.
107 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.
108 Menegon, S., Columbano, A. and Giordano, S. (2016) The dual roles of NRF2 in cancer. Trends Mol. Med. 22, 578-593.   DOI
109 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.   DOI
110 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.   DOI
111 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.   DOI
112 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.   DOI
113 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.   DOI
114 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.   DOI
115 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.
116 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.   DOI
117 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.   DOI
118 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.   DOI
119 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.   DOI
120 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.   DOI
121 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.
122 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.   DOI
123 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.
124 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.   DOI
125 Kwak, M.-K. and Kensler, T. W. (2010) Targeting NRF2 signaling for cancer chemoprevention. Toxicol. Appl. Pharmacol. 244, 66-76.   DOI
126 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.   DOI
127 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.   DOI
128 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.
129 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].   DOI
130 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.   DOI