Cytoprotection "gone astray": Nrf2 and its role in cancer

OncoTargets and Therapy

Volumn 7, Issue , 2014, Pages 1497-1518

  Geismann, Claudia ^a   Arlt, Alexander ^a   Sebens, Susanne ^a   Schäfer, Heiner ^a  

^a UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

Author keywords

Cancer therapy; Carcinogen; Transcription factor; Tumorigenesis; Xenobiotic and oxidative stress

Indexed keywords

B RAF KINASE; BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR; CAVEOLIN; ESTROGEN; ESTROGEN RECEPTOR; HYPOXIA INDUCIBLE FACTOR 1ALPHA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; K RAS PROTEIN; KELCH LIKE ECH ASSOCIATED PROTEIN 1; MAMMALIAN TARGET OF RAPAMYCIN; NOTCH RECEPTOR; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEASOME; PROTEIN BCL 2; PROTEIN BCL XL; PROTEIN KINASE B; PROTEIN P53; RECOMBINANT TRANSFORMING GROWTH FACTOR BETA1; TRANSCRIPTION FACTOR NRF2; UBIQUITIN;

ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; ARTICLE; AUTOPHAGY; CANCER GROWTH; CANCER INHIBITION; CANCER PROGNOSIS; CANCER RADIOTHERAPY; CANCER RESISTANCE; CANCER THERAPY; CARCINOGENESIS; CARCINOGENIC ACTIVITY; CELL PROTECTION; EPITHELIAL MESENCHYMAL TRANSITION; HUMAN; METABOLISM; MOLECULAR DYNAMICS; NEOPLASM; NONHUMAN; ONCOGENE; ONCOGENE BRAF; ONCOGENE K RAS; ONCOGENE MYC; ONCOGENE NRF2; OXIDATIVE STRESS; REGULATORY MECHANISM; SIGNAL TRANSDUCTION; TUMOR INVASION; TUMOR VASCULARIZATION; XENOBIOTIC STRESS;

EID: 84907337366     PISSN: None     EISSN: 11786930     Source Type: Journal    
DOI: 10.2147/OTT.S36624     Document Type: Article

References (282)

1. Kang KW, Lee SJ, Kim S.G. Molecular mechanism of nrf2 activation by oxidative stress. Antioxid Redox Signal. 2005;7(11-12): 1664-1673.
2. Osburn WO, Kensler T.W. Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults. Mutat Res. 2008;659(1-2):31-39.
3. Kaspar JW, Niture SK, Jaiswal A.K. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med. 2009;47(9):1304-1309.
4. Suzuki T, Motohashi H, Yamamoto M. Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol Sci. 2013;34(6): 340-346.
5. Giudice A, Montella M. Activation of the Nrf2-ARE signaling pathway: a promising strategy in cancer prevention. Bioessays. 2006;28(2): 169-181.
6. Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang D.D. Dual roles of Nrf2 in cancer. Pharmacol Res. 2008;58(5-6):262-270.
7. Kwak MK, Kensler T.W. Targeting NRF2 signaling for cancer chemoprevention. Toxicol Appl Pharmacol. 2010;244(1):66-76.
8. Hayes JD, McMahon M, Chowdhry S, Dinkova-Kostova A.T. Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid Redox Signal. 2010;13(11):1713-1748.
9. Sporn MB, Liby K.T. NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer. 2012;12(8):564-571.
10. Jaramillo MC, Zhang D.D. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev. 2013;27(20):2179-2191.
11. Shelton P, Jaiswal A.K. The transcription factor NF-E2-related factor 2 (Nrf2): a protooncogene? FASEB J. 2013;27(2):414-423.
12. Zhang D.D. The Nrf2-Keap1-ARE signaling pathway: The regulation and dual function of Nrf2 in cancer. Antioxid Redox Signal. 2010;13(11): 1623-1626.
13. DeNicola GM, Karreth FA, Humpton TJ, et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 2011;475(7354):106-109.
14. Cadenas E. Biochemistry of oxygen toxicity. Annu Rev Biochem. 1989;58:79-110.
15. Halliwell B, Gutteridge J.M. Free Radicals in Biology and Medicine. 3rd ed. Oxford: Oxford University Press; 1999.
16. Inoue M, Sato EF, Nishikawa M, et al. Mitochondrial generation of reactive oxygen species and its role in aerobic life. Curr Med Chem. 2003;10(23):2495-2505.
17. Conner EM, Grisham M.B. Inflammation, free radicals, and antioxidants. Nutrition. 1996;12(4):274-277.
18. Poli G, Leonarduzzi G, Biasi F, Chiarpotto E. Oxidative stress and cell signalling. Curr Med Chem. 2004;11(9):1163-1182.
19. Knight J.A. Diseases related to oxygen-derived free radicals. Ann Clin Lab Sci. 1995;25(2):111-121.
20. Klaunig JE, Kamendulis L.M. The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol. 2004;44:239-267.
21. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal B.B. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49(11):1603-1616.
22. Cho HY, Reddy SP, Kleeberger S.R. Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal. 2006;8(1-2):76-87.
23. Nguyen T, Nioi P, Pickett C.B. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284(20):13291-13295.
24. Chorley BN, Campbell MR, Wang X, et al. Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res. 2012;40(15):7416-7429.
25. Malhotra D, Portales-Casamar E, Singh A, et al. Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res. 2010;38(17):5718-5734.
26. Johnson CH, Patterson AD, Idle JR, Gonzalez F.J. Xenobiotic metabolomics: major impact on the metabolome. Annu Rev Pharmacol Toxicol. 2012;52:37-56.
27. Idle JR, Gonzalez F.J. Metabolomics. Cell Metab. 2007;6(5): 348-351.
28. Williams GM, Jeffrey A.M. Oxidative DNA damage: endogenous and chemically induced. Regul Toxicol Pharmacol. 2000;32(3): 283-292.
29. Li X, Schuler MA, Berenbaum M.R. Molecular mechanisms of metabolic resistance to synthetic and natural xenobiotics. Annu Rev Entomol. 2007;52:231-253.
30. Lewis D.F. Human P450s in the metabolism of drugs: molecular modelling of enzyme-substrate interactions. Expert Opin Drug Metab Toxicol. 2005;1(1):5-8.
31. Xu C, Li CY, Kong A.N. Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch Pharm Res. 2005;28(3):249-268.
32. Hayes JD, Dinkova-Kostova A.T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2014;39(4):199-218.
33. Hirotsu Y, Katsuoka F, Funayama R, et al. Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res. 2012;40(20):10228-10239.
34. Moi P, Chan K, Asunis I, Cao A, Kan Y.W. 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. 1994;91(21): 9926-9930.
35. Itoh K, Wakabayashi N, Katoh Y, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13(1):76-86.
36. Cullinan SB, Gordan JD, Jin J, Harper JW, Diehl J.A. The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Mol Cell Biol. 2004;24(19):8477-8486.
37. Katoh Y, Iida K, Kang MI, et al. Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome. Arch Biochem Biophys. 2005;433(2): 342-350.
38. Kobayashi A, Kang MI, Watai Y, et al. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol. 2006;26(1):221-229.
39. Tong KI, Kobayashi A, Katsuoka F, Yamamoto M. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. Biol Chem. 2006;387(10-11):1311-1320.
40. Rachakonda G, Xiong Y, Sekhar KR, Stamer SL, Liebler DC, Freeman M.L. Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chem Res Toxicol. 2008;21(3):705-710.
41. Zhang DD, Lo SC, Sun Z, Habib GM, Lieberman MW, Hannink M. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. J Biol Chem. 2005;280(34):30091-30099.
42. Villeneuve NF, Tian W, Wu T, et al. USP15 negatively regulates Nrf2 through deubiquitination of Keap1. Mol Cell. 2013;51(1):68-79.
43. Niture SK, Kaspar JW, Shen J, Jaiswal A.K. Nrf2 signaling and cell survival. Toxicol Appl Pharmacol. 2010;244(1):37-42.
44. Huang HC, Nguyen T, Pickett C.B. Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. Proc Natl Acad Sci U S.A. 2000;97(23):12475-12480.
45. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl J.A. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol. 2003;23(20):7198-7209.
46. Apopa PL, He X, Ma Q. Phosphorylation of Nrf2 in the transcription activation domain by casein kinase 2 (CK2) is critical for the nuclear translocation and transcription activation function of Nrf2 in IMR-32 neuroblastoma cells. J Biochem Mol Toxicol. 2008;22(1):63-76.
47. Sun Z, Chin YE, Zhang D.D. Acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 during the antioxidant response. Mol Cell Biol. 2009;29(10):2658-2672.
48. Chen Z, Ye X, Tang N, et al. The histone acetylranseferase [sic] hMOF acetylates Nrf2 and regulates anti-drug responses in human non-small cell lung cancer. Br J Pharmacol. 2014;171(13):3196-3211.
49. Kawai Y, Garduno L, Theodore M, Yang J, Arinze I.J. Acetylation-deacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic localization. J Biol Chem. 2011;286(9):7629-7640.
50. Kang SJ, Ryoo IG, Lee YJ, Kwak M.K. Role of the Nrf2-heme oxygenase-1 pathway in silver nanoparticle-mediated cytotoxicity. Toxicol Appl Pharmacol. 2012;258(1):89-98.
51. Yu R, Chen C, Mo YY, et al. Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism. J Biol Chem. 2000;275(51):39907-39913.
52. Yu R, Mandlekar S, Lei W, Fahl WE, Tan TH, Kong A.N. p38 Mitogen-activated protein kinase negatively regulates the induction of phase II drug-metabolizing enzymes that detoxify carcinogens. J Biol Chem. 2000;275(4):2322-2327.
53. Sakamoto K, Iwasaki K, Sugiyama H, Tsuji Y. Role of the tumor suppressor PTEN in antioxidant responsive element-mediated transcription and associated histone modifications. Mol Biol Cell. 2009;20(6):1606-1617.
54. Jain AK, Jaiswal A.K. GSK-3β acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2. J Biol Chem. 2007;282(22):16502-16510.
55. Blank V. Small Maf proteins in mammalian gene control: mere dimerization partners or dynamic transcriptional regulators? J Mol Biol. 2008;376(4):913-925.
56. Motohashi H, Shavit JA, Igarashi K, Yamamoto M, Engel J.D. The world according to Maf. Nucleic Acids Res. 1997;25(15):2953-2959.
57. Kannan MB, Solovieva V, Blank V. The small MAF transcription factors MAFF, MAFG and MAFK: current knowledge and perspectives. Biochim Biophys Acta. 2012;1823(10):1841-1846.
58. Benkhelifa S, Provot S, Nabais E, Eychène A, Calothy G, Felder-Schmittbuhl M.P. Phosphorylation of MafA is essential for its transcriptional and biological properties. Mol Cell Biol. 2001;21(14): 4441-4452.
59. Sii-Felice K, Pouponnot C, Gillet S, et al. MafA transcription factor is phosphorylated by p38 MAP kinase. FEBS Lett. 2005;579(17): 3547-3554.
60. Ro YT, Jang BK, Shin CY, Park EU, Kim CG, Yang S.I. Akt regulates the expression of MafK, synaptotagmin I, and syntenin-1, which play roles in neuronal function. J Biomed Sci. 2010;17:18.
61. Tanigawa S, Lee CH, Lin CS, et al. Jun dimerization protein 2 is a critical component of the Nrf2/MafK complex regulating the response to ROS homeostasis. Cell Death Dis. 2013;4:e921.
62. Oyake T, Itoh K, Motohashi H, et al. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol Cell Biol. 1996;16(11):6083-6095.
63. Hoshino H, Kobayashi A, Yoshida M, et al. Oxidative stress abolishes leptomycin B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element. J Biol Chem. 2000;275(20):15370-15376.
64. Dhakshinamoorthy S, Jain AK, Bloom DA, Jaiswal A.K. Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants. J Biol Chem. 2005;280(17):16891-16900.
65. Jyrkkänen HK, Kuosmanen S, Heinäniemi M, et al. Novel insights into the regulation of antioxidant-response-element-mediated gene expression by electrophiles: induction of the transcriptional repressor BACH1 by Nrf2. Biochem J. 2011;440(2):167-174.
66. Mitsuishi Y, Taguchi K, Kawatani Y, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012;22(1):66-79.
67. Niture SK, Khatri R, Jaiswal A.K. Regulation of Nrf2-an update. Free Radic Biol Med. 2014;66:36-44.
68. Mitsuishi Y, Motohashi H, Yamamoto M. The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism. Front Oncol. 2012;2:200.
69. Zhang DD, Hannink M. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol. 2003;23(22):8137-8151.
70. Yamamoto T, Suzuki T, Kobayashi A, et al. Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol. 2008;28(8):2758-2770.
71. Magesh S, Chen Y, Hu L. Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med Res Rev. 2012;32(4):687-726.
72. Kumar H, Kim IS, More SV, Kim BW, Choi D.K. Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases. Nat Prod Rep. 2014;31(1):109-139.
73. Lo SC, Hannink M. PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria. Exp Cell Res. 2008;314(8):1789-1803.
74. Niture SK, Jaiswal A.K. Inhibitor of Nrf2 (INrf2 or Keap1) protein degrades Bcl-xL via phosphoglycerate mutase 5 and controls cellular apoptosis. J Biol Chem. 2011;286(52):44542-44556.
75. Komatsu M, Kurokawa H, Waguri S, et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010;12(3):213-223.
76. Inami Y, Waguri S, Sakamoto A, et al. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol. 2011;193(2):275-284.
77. Chen W, Sun Z, Wang XJ, et al. Direct interaction between Nrf2 and p21 (Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response. Mol Cell. 2009;34(6):663-673.
78. Chowdhry S, Zhang Y, McMahon M, Sutherland C, Cuadrado A, Hayes J.D. 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. 2013;32(32):3765-3781.
79. Rada P, Rojo AI, Evrard-Todeschi N, et al. Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/beta-TrCP axis. Mol Cell Biol. 2012;32(17):3486-3499.
80. Faraonio R, Vergara P, Di Marzo D, et al. p53 Suppresses the Nrf2-dependent transcription of antioxidant response genes. J Biol Chem. 2006;281(52):39776-39784.
81. Chen W, Jiang T, Wang H, et al. Does Nrf2 contribute to p53-mediated control of cell survival and death? Antioxid Redox Signal. 2012;17(12):1670-1675.
82. Kalo E, Kogan-Sakin I, Solomon H, et al. Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high levels of reactive oxygen species. J Cell Sci. 2012;125(Pt 22):5578-5586.
83. Niture SK, Jain AK, Shelton PM, Jaiswal A.K. Src subfamily kinases regulate nuclear export and degradation of transcription factor Nrf2 to switch off Nrf2-mediated antioxidant activation of cytoprotective gene expression. J Biol Chem. 2011;286(33):28821-28832.
84. Sun Z, Zhang S, Chan JY, Zhang D.D. Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2. Mol Cell Biol. 2007;27(18):6334-6349.
85. Yu M, Li H, Liu Q, et al. Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway. Cell Signal. 2011;23(5):883-892.
86. Kim WD, Kim YW, Cho IJ, Lee CH, Kim S.G. E-cadherin inhibits nuclear accumulation of Nrf2: implications for chemoresistance of cancer cells. J Cell Sci. 2012;125(Pt 5):1284-1295.
87. Bakin AV, Stourman NV, Sekhar KR, et al. Smad3-ATF3 signaling mediates TGF-beta suppression of genes encoding phase II detoxifying proteins. Free Radic Biol Med. 2005;38(3):375-387.
88. Brown SL, Sekhar KR, Rachakonda G, Sasi S, Freeman M.L. Activating transcription factor 3 is a novel repressor of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)-regulated stress pathway. Cancer Res. 2008;68(2):364-368.
89. Kratschmar DV, Calabrese D, Walsh J, et al. Suppression of the Nrf2-dependent antioxidant response by glucocorticoids and 11β-HSD1-mediated glucocorticoid activation in hepatic cells. PLoS One. 2012;7(5):e36774.
90. Zhou W, Lo SC, Liu JH, Hannink M, Lubahn D.B. ERRβ: a potent inhibitor of Nrf2 transcriptional activity. Mol Cell Endocrinol. 2007;278(1-2):52-62.
91. Yao Y, Brodie AM, Davidson NE, Kensler TW, Zhou Q. Inhibition of estrogen signaling activates the NRF2 pathway in breast cancer. Breast Cancer Res Treat. 2010;124(2):585-591.
92. Wang XJ, Hayes JD, Henderson CJ, 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 U S.A. 2007;104(49):19589-19594.
93. Wang H, Liu K, Geng M, et al. RXRα inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2. Cancer Res. 2013;73(10):3097-3108.
94. Bryan HK, Olayanju A, Goldring CE, Park B.K. The Nrf2 cell defence pathway: Keap1-dependent and-independent mechanisms of regulation. Biochem Pharmacol. 2013;85(6):705-717.
95. Gañán-Gómez I, Wei Y, Yang H, Boyano-Adánez MC, García-Manero G. Oncogenic functions of the transcription factor Nrf2. Free Radic Biol Med. 2013;65:750-764.
96. Slocum SL, Kensler T.W. Nrf2: control of sensitivity to carcinogens. Arch Toxicol. 2011;85(4):273-284.
97. Chan K, Lu R, Chang JC, Kan Y.W. NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci U S.A. 1996;93(24):13943-13948.
98. Cho HY, Kleeberger S.R. Nrf2 protects against airway disorders. Toxicol Appl Pharmacol. 2010;244(1):43-56.
99. Kudoh K, Uchinami H, Yoshioka M, Seki E, Yamamoto Y. Nrf2 activation protects the liver from ischemia/reperfusion injury in mice. Ann Surg. 2014;260(1):118-127.
100. Liu M, Reddy NM, Higbee EM, et al. The Nrf2 triterpenoid activator, CDDO-imidazolide, protects kidneys from ischemia-reperfusion injury in mice. Kidney Int. 2014;85(1):134-141.
101. Shirasaki K, Taguchi K, Unno M, Motohashi H, Yamamoto M. NF-E2-related factor 2 promotes compensatory liver hypertrophy after portal vein branch ligation in mice. Hepatology. 2014;59(6): 2371-2382.
102. Zhao Z, Chen Y, Wang J, et al. Age-related retinopathy in NRF2-deficient mice. PLoS One. 2011;6(4):e19456.
103. Osburn WO, Karim B, Dolan PM, et al. Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment. Int J Cancer. 2007;121(9): 1883-1891.
104. Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS, Kong A.N. Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res. 2006;66(24):11580-11584.
105. Khor TO, Huang MT, Prawan A, et al. Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer. Cancer Prev Res (Phila). 2008;1(3):187-191.
106. Iida K, Itoh K, Kumagai Y, et al. Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res. 2004;64(18):6424-6431.
107. Liby KT, Royce DB, Risingsong R, et al. Synthetic triterpenoids prolong survival in a transgenic mouse model of pancreatic cancer. Cancer Prev Res (Phila). 2010;3(11):1427-1434.
108. Saw CL, Huang MT, Liu Y, Khor TO, Conney AH, Kong A.N. Impact of Nrf2 on UVB-induced skin inflammation/photoprotection and photoprotective effect of sulforaphane. Mol Carcinog. 2011;50(6):479-486.
109. Xu C, Huang MT, Shen G, et al. Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2. Cancer Res. 2006;66(16):8293-8296.
110. Yates MS, Kwak MK, Egner PA, et al. Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole. Cancer Res. 2006; 66(4):2488-2494.
111. McMahon M, Itoh K, Yamamoto M, et al. The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res. 2001;61(8):3299-3307.
112. Ramos-Gomez M, Dolan PM, Itoh K, Yamamoto M, Kensler T.W. Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice. Carcinogenesis. 2003;24(3): 461-467.
113. Shen G, Xu C, Hu R, et al. Modulation of nuclear factor E2-related factor 2-mediated gene expression in mice liver and small intestine by cancer chemopreventive agent curcumin. Mol Cancer Ther. 2006;5(1):39-51.
114. Sussan TE, Rangasamy T, Blake DJ, et al. Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc Natl Acad Sci U S.A. 2009;106(1):250-255.
115. Zheng H, Whitman SA, Wu W, et al. Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes. 2011;60(11):3055-3066.
116. Ramos-Gomez M, Kwak MK, Dolan PM, et al. 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. 2001;98(6):3410-3415.
117. Cheung KL, Lee JH, Khor TO, et al. Nrf2 knockout enhances intestinal tumorigenesis in Apc(min/+) mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation. Mol Carcinog. 2014;53(1):77-84.
118. Satoh H, Moriguchi T, Taguchi K, et al. Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung. Carcinogenesis. 2010;31(10):1833-1843.
119. Schultz MA, Hagan SS, Datta A, et al. Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells. PLoS One. 2014;9(1):e87204.
120. Wang W, Kwok AM, Chan J.Y. The p65 isoform of Nrf1 is a dominant negative inhibitor of ARE-mediated transcription. J Biol Chem. 2007;282(34):24670-24678.
121. Kundu JK, Surh Y.J. Nrf2-Keap1 signaling as a potential target for chemoprevention of inflammation-associated carcinogenesis. Pharm Res. 2010;27(6):999-1013.
122. Liu J, Gu X, Robbins D, et al. Protandim, a fundamentally new antioxidant approach in chemoprevention using mouse two-stage skin carcinogenesis as a model. PLoS One. 2009;4(4):e5284.
123. Zhao CR, Gao ZH, Qu X.J. Nrf2-ARE signaling pathway and natural products for cancer chemoprevention. Cancer Epidemiol. 2010;34(5): 523-533.
124. Ashrafian H, Czibik G, Bellahcene M, et al. Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. Cell Metab. 2012;15(3):361-371.
125. Chartoumpekis DV, Ziros PG, Psyrogiannis AI, et al. Nrf2 represses FGF21 during long-term high-fat diet-induced obesity in mice. Diabetes. 2011;60(10):2465-2473.
126. Johnson JA, Johnson DA, Kraft AD, et al. The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Ann N Y Acad Sci. 2008;1147:61-69.
127. LaPash Daniels CM, Austin EV, Rockney DE, et al. Beneficial effects of Nrf2 overexpression in a mouse model of Alexander disease. J Neurosci. 2012;32(31):10507-10515.
128. Uruno A, Furusawa Y, Yagishita Y, et al. The Keap1-Nrf2 system prevents onset of diabetes mellitus. Mol Cell Biol. 2013;33(15): 2996-3010.
129. Kensler TW, Egner PA, Agyeman AS, et al. Keap1-nrf2 signaling: a target for cancer prevention by sulforaphane. Top Curr Chem. 2013;329:163-177.
130. Cornblatt BS, Ye L, Dinkova-Kostova AT, et al. Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast. Carcinogenesis. 2007;28(7):1485-1490.
131. Egner PA, Chen JG, Wang JB, et al. Bioavailability of sulforaphane from two broccoli sprout beverages: results of a short-term, cross-over clinical trial in Qidong, China. Cancer Prev Res (Phila). 2011;4(3): 384-395.
132. Kensler TW, Ng D, Carmella SG, et al. Modulation of the metabolism of airborne pollutants by glucoraphanin-rich and sulforaphane-rich broccoli sprout beverages in Qidong, China. Carcinogenesis. 2012;33(1):101-107.
133. Zoja C, Benigni A, Remuzzi G. The Nrf2 pathway in the progression of renal disease. Nephrol Dial Transplant. 2014;29 Suppl 1: i19-i24.
134. Reddy NM, Potteti HR, Mariani TJ, Biswal S, Reddy S.P. Conditional deletion of Nrf2 in airway epithelium exacerbates acute lung injury and impairs the resolution of inflammation. Am J Respir Cell Mol Biol. 2011;45(6):1161-1168.
135. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells. 2011;16(2):123-140.
136. Lister A, Nedjadi T, Kitteringham NR, et al. Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy. Mol Cancer. 2011;10:37.
137. Soini Y, Eskelinen M, Juvonen P, et al. Nuclear Nrf2 expression is related to a poor survival in pancreatic adenocarcinoma. Pathol Res Pract. 2014;210(1):35-39.
138. Arlt A, Sebens S, Krebs S, 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. 2013;32(40): 4825-4835.
139. Garcia-Manero G, Tambaro FP, Bekele NB, et al. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol. 2012;30(18):2204-2210.
140. Chen N, Yi X, Abushahin N, et al. Nrf2 expression in endometrial serous carcinomas and its precancers. Int J Clin Exp Pathol. 2010;4(1):85-96.
141. Barbano R, Muscarella LA, Pasculli B, et al. Aberrant Keap1 methylation in breast cancer and association with clinicopathological features. Epigenetics. 2013;8(1):105-112.
142. Al Saati T, Clerc P, Hanoun N, et al. Oxidative stress induced by inactivation of TP53INP1 cooperates with KrasG12D to initiate and promote pancreatic carcinogenesis in the murine pancreas. Am J Pathol. 2013;182(6):1996-2004.
143. Petrelli A, Perra A, Cora D, et al. MicroRNA/gene profiling unveils early molecular changes and nuclear factor erythroid related factor 2 (NRF2) activation in a rat model recapitulating human hepatocellular carcinoma (HCC). Hepatology. 2014;59(1):228-241.
144. Ma Q, He X. Molecular basis of electrophilic and oxidative defense: promises and perils of Nrf2. Pharmacol Rev. 2012;64(4): 1055-1081.
145. Yoo NJ, Kim HR, Kim YR, An CH, Lee S.H. Somatic mutations of the KEAP1 gene in common solid cancers. Histopathology. 2012;60(6):943-952.
146. Hast BE, Cloer EW, Goldfarb D, et al. Cancer-derived mutations in KEAP1 impair NRF2 degradation but not ubiquitination. Cancer Res. 2014;74(3):808-817.
147. Shibata T, Ohta T, Tong KI, et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S.A. 2008;105(36):13568-13573.
148. Kim YR, Oh JE, Kim MS, et al. Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J Pathol. 2010;220(4):446-451.
149. Solis LM, Behrens C, Dong W, et al. Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin Cancer Res. 2010;16(14):3743-3753.
150. Wang R, An J, Ji F, Jiao H, Sun H, Zhou D. Hypermethylation of the Keap1 gene in human lung cancer cell lines and lung cancer tissues. Biochem Biophys Res Commun. 2008;373(1):151-154.
151. Hanada N, Takahata T, Zhou Q, et al. Methylation of the KEAP1 gene promoter region in human colorectal cancer. BMC Cancer. 2012;12:66.
152. Zhang P, Singh A, Yegnasubramanian S, et al. Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Mol Cancer Ther. 2010;9(2):336-346.
153. Yu S, Khor TO, Cheung KL, et al. Nrf2 expression is regulated by epigenetic mechanisms in prostate cancer of TRAMP mice. PLoS One. 2010;5(1):e8579.
154. Khor TO, Huang Y, Wu TY, Shu L, Lee J, Kong A.N. Pharmacodynamics of curcumin as DNA hypomethylation agent in restoring the expression of Nrf2 via promoter CpGs demethylation. Biochem Pharmacol. 2011;82(9):1073-1078.
155. Du W, Jiang Y, Zheng Z, et al. Feedback loop between p66(Shc) and Nrf2 promotes lung cancer progression. Cancer Lett. 2013;337(1): 58-65.
156. Eades G, Yang M, Yao Y, Zhang Y, Zhou Q. miR-200a regulates Nrf2 activation by targeting Keap1 mRNA in breast cancer cells. J Biol Chem. 2011;286(47):40725-40733.
157. van Jaarsveld MT, Helleman J, Boersma AW, et al. miR-141 regulates KEAP1 and modulates cisplatin sensitivity in ovarian cancer cells. Oncogene. 2013;32(36):4284-4293.
158. Yang M, Yao Y, Eades G, Zhang Y, Zhou Q. MiR-28 regulates Nrf2 expression through a Keap1-independent mechanism. Breast Cancer Res Treat. 2011;129(3):983-991.
159. Yamamoto S, Inoue J, Kawano T, Kozaki K, Omura K, Inazawa J. The impact of miRNA-based molecular diagnostics and treatment of NRF2-stabilized tumors. Mol Cancer Res. 2014;12(1):58-68.
160. Adam J, Hatipoglu E, O'Flaherty L, et al. 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. 2011;20(4):524-537.
161. Kinch L, Grishin NV, Brugarolas J. Succination of Keap1 and activation of Nrf2-dependent antioxidant pathways in FH-deficient papillary renal cell carcinoma type 2. Cancer Cell. 2011;20(4): 418-420.
162. Kong B, Qia C, Erkan M, Kleeff J, Michalski C.W. Overview on how oncogenic Kras promotes pancreatic carcinogenesis by inducing low intracellular ROS levels. Front Physiol. 2013;4:246.
163. Satoh H, Moriguchi T, Takai J, Ebina M, Yamamoto M. Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis. Cancer Res. 2013;73(13): 4158-4168.
164. Bauer AK, Hill T 3rd, Alexander C.M. The involvement of NRF2 in lung cancer. Oxid Med Cell Longev. 2013;2013:746432.
165. Yamadori T, Ishii Y, Homma S, et al. Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers. Oncogene. 2012;31(45):4768-4777.
166. Banerjee P, Basu A, Datta D, Gasser M, Waaga-Gasser AM, Pal S. The heme oxygenase-1 protein is overexpressed in human renal cancer cells following activation of the Ras-Raf-ERK pathway and mediates anti-apoptotic signal. J Biol Chem. 2011;286(38): 33580-33590.
167. Funes JM, Henderson S, Kaufman R, et al. Oncogenic transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer survival. Mol Cancer. 2014;13(1):20.
168. Nagy P, Varga A, Pircs K, Hegedus K, Juhász G. Myc-driven overgrowth requires unfolded protein response-mediated induction of autophagy and antioxidant responses in Drosophila melanogaster. PLoS Genet. 2013;9(8):e1003664.
169. Levy S, Forman H.J. C-Myc is a Nrf2-interacting protein that negatively regulates phase II genes through their electrophile responsive elements. IUBMB Life. 2010;62(3):237-246.
170. Romano G. The role of the dysfunctional Akt-related pathway in cancer: establishment and maintenance of a malignant cell phenotype, resistance to therapy, and future strategies for drug development. Scientifica (Cairo). 2013;2013:317186.
171. Gao AM, Ke ZP, Shi F, Sun GC, Chen H. Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway. Chem Biol Interact. 2013;206(1): 100-108.
172. Deng X, Rui W, Zhang F, Ding W. PM2.5 induces Nrf2-mediated defense mechanisms against oxidative stress by activating PIK3/AKT signaling pathway in human lung alveolar epithelial A549 cells. Cell Biol Toxicol. 2013;29(3):143-157.
173. Stachel I, Geismann C, Aden K, et al. Modulation of nuclear factor E2-related factor-2 (Nrf2) activation by the stress response gene immediate early response-3 (IER3) in colonic epithelial cells: a novel mechanism of cellular adaption to inflammatory stress. J Biol Chem. 2014;289(4):1917-1929.
174. Taguchi K, Sakata K, Ohashi W, Imaizumi T, Imamura J, Hattori Y. Tonic inhibition by G protein-coupled receptor kinase 2 of Akt/endothelial nitric oxide synthase signaling in human vascular endothelial cells under conditions of hyperglycemia with high insulin levels. J Pharmacol Exp Ther. 2014;349(2):199-208.
175. Dey N, Crosswell HE, De P, et al. The protein phosphatase activity of PTEN regulates SRC family kinases and controls glioma migration. Cancer Res. 2008;68(6):1862-1871.
176. Huang W, Lv X, Liu C, et al. The N-terminal phosphodegron targets TAZ/WWTR1 protein for SCFβ-TrCP-dependent degradation in response to phosphatidylinositol 3-kinase inhibition. J Biol Chem. 2012;287(31):26245-26253.
177. Chen Q, Li W, Wan Y, et al. Amplified in breast cancer 1 enhances human cholangiocarcinoma growth and chemoresistance by simultaneous activation of Akt and Nrf2 pathways. Hepatology. 2012;55(6): 1820-1829.
178. Lerner C, Bitto A, Pulliam D, et al. Reduced mammalian target of rapamycin activity facilitates mitochondrial retrograde signaling and increases life span in normal human fibroblasts. Aging Cell. 2013;12(6):966-977.
179. Shibata T, Saito S, Kokubu A, Suzuki T, Yamamoto M, Hirohashi S. Global downstream pathway analysis reveals a dependence of oncogenic NF-E2-related factor 2 mutation on the mTOR growth signaling pathway. Cancer Res. 2010;70(22):9095-9105.
180. Gaikwad NW, Yang L, Rogan EG, Cavalieri E.L. Evidence for NQO2-mediated reduction of the carcinogenic estrogen ortho-quinones. Free Radic Biol Med. 2009;46(2):253-262.
181. Ansell PJ, Lo SC, Newton LG, et al. Repression of cancer protective genes by 17β-estradiol: ligand-dependent interaction between human Nrf2 and estrogen receptor alpha. Mol Cell Endocrinol. 2005;243(1-2):27-34.
182. Lo R, Matthews J. The aryl hydrocarbon receptor and estrogen receptor alpha differentially modulate nuclear factor erythroid-2-related factor 2 transactivation in MCF-7 breast cancer cells. Toxicol Appl Pharmacol. 2013;270(2):139-148.
183. Lam SS, Mak AS, Yam JW, Cheung AN, Ngan HY, Wong A.S. Targeting estrogen-related receptor alpha inhibits epithelial-to-mesenchymal transition and stem cell properties of ovarian cancer cells. Mol Ther. 2014;22(4):743-751.
184. Zhang T, Liang X, Shi L, et al. Estrogen receptor and PI3K/Akt signaling pathway involvement in S-(-)equol-induced activation of Nrf2/ARE in endothelial cells. PLoS One. 2013;8(11):e79075.
185. Gorrini C, Gang BP, Bassi C, et al. Estrogen controls the survival of BRCA1-deficient cells via a PI3K-NRF2-regulated pathway. Proc Natl Acad Sci U S.A. 2014;111(12):4472-4477.
186. Montano MM, Deng H, Liu M, Sun X, Singal R. Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications. Oncogene. 2004;23(14):2442-2453.
187. Arlt A, Schäfer H, Kalthoff H. The 'N-factors' in pancreatic cancer: functional relevance of NF-κB, NFAT and Nrf2 in pancreatic cancer. Oncogenesis. 2012;1:e35.
188. Wakabayashi N, Slocum SL, Skoko JJ, Shin S, Kensler T.W. When NRF2 talks, who's listening? Antioxid Redox Signal. 2010;13(11): 1649-1663.
189. Liu GH, Qu J, Shen X. NF-κB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK. Biochim Biophys Acta. 2008;1783(5):713-727.
190. Healy ZR, Lee NH, Gao X, et al. Divergent responses of chondrocytes and endothelial cells to shear stress: cross-talk among COX-2, the phase 2 response, and apoptosis. Proc Natl Acad Sci U S.A. 2005;102(39):14010-14015.
191. Chen CY, Jang JH, Li MH, Surh Y.J. Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells. Biochem Biophys Res Commun. 2005;331(4):993-1000.
192. Manna SK, Mukhopadhyay A, Aggarwal B.B. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol. 2000;164(12):6509-6519.
193. Balogun E, Foresti R, Green CJ, Motterlini R. Changes in temperature modulate heme oxygenase-1 induction by curcumin in renal epithelial cells. Biochem Biophys Res Commun. 2003;308(4):950-955.
194. Gan FF, Ling H, Ang X, et al. A novel shogaol analog suppresses cancer cell invasion and inflammation, and displays cytoprotective effects through modulation of NF-κB and Nrf2-Keap1 signaling pathways. Toxicol Appl Pharmacol. 2013;272(3):852-862.
195. Kumar S, Singh BK, Prasad AK, Parmar VS, Biswal S, Ghosh B. Ethyl 3′,4′,5′-trimethoxythionocinnamate modulates NF-κB and Nrf2 transcription factors. Eur J Pharmacol. 2013;700(1-3):32-41.
196. Rushworth SA, Zaitseva L, Murray MY, Shah NM, Bowles KM, MacEwan D.J. The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance. Blood. 2012;120(26):5188-5198.
197. Arlt A, Bauer I, Schafmayer C, et al. Increased proteasome subunit protein expression and proteasome activity in colon cancer relate to an enhanced activation of nuclear factor E2-related factor 2 (Nrf2). Oncogene. 2009;28(45):3983-3996.
198. Niture SK, Jaiswal A.K. Nrf2-induced antiapoptotic Bcl-xL protein enhances cell survival and drug resistance. Free Radic Biol Med. 2013;57:119-131.
199. Niture SK, Jaiswal A.K. Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J Biol Chem. 2012;287(13):9873-9886.
200. Rotblat B, Melino G, Knight R.A. NRF2 and p53: Januses in cancer? Oncotarget. 2012;3(11):1272-1283.
201. Vurusaner B, Poli G, Basaga H. Tumor suppressor genes and ROS: complex networks of interactions. Free Radic Biol Med. 2012;52(1):7-18.
202. Suzuki S, Tanaka T, Poyurovsky MV, et al. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci U S.A. 2010;107(16): 7461-7466.
203. Bensaad K, Tsuruta A, Selak MA, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006;126(1):107-120.
204. Asher G, Lotem J, Kama R, Sachs L, Shaul Y. NQO1 stabilizes p53 through a distinct pathway. Proc Natl Acad Sci U S.A. 2002;99(5): 3099-3104.
205. You A, Nam CW, Wakabayashi N, Yamamoto M, Kensler TW, Kwak M.K. Transcription factor Nrf2 maintains the basal expression of Mdm2: an implication of the regulation of p53 signaling by Nrf2. Arch Biochem Biophys. 2011;507(2):356-364.
206. Capaccione KM, Pine S.R. The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis. 2013;34(7):1420-1430.
207. Wakabayashi N, Skoko JJ, Chartoumpekis DV, et al. Notch-Nrf2 axis: regulation of Nrf2 gene expression and cytoprotection by notch signaling. Mol Cell Biol. 2014;34(4):653-663.
208. Kim JH, Thimmulappa RK, Kumar V, et al. NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation. J Clin Invest. 2014;124(2):730-741.
209. Zhu J, Wang H, Sun Q, et al. Nrf2 is required to maintain the self-renewal of glioma stem cells. BMC Cancer. 2013;13:380.
210. Li W, Liu H, Zhou JS, et al. Caveolin-1 inhibits expression of antioxidant enzymes through direct interaction with nuclear erythroid 2 p45-related factor-2 (Nrf2). J Biol Chem. 2012;287(25): 20922-20930.
211. Zheng Y, Morris A, Sunkara M, Layne J, Toborek M, Hennig B. Epigallocatechin-gallate stimulates NF-E2-related factor and heme oxygenase-1 via caveolin-1 displacement. J Nutr Biochem. 2012;23(2):163-168.
212. Volonte D, Liu Z, Musille PM, et al. Inhibition of nuclear factor-erythroid 2-related factor (Nrf2) by caveolin-1 promotes stress-induced premature senescence. Mol Biol Cell. 2013;24(12):1852-1862.
213. Cosset EC, Godet J, Entz-Werle N, et al. Involvement of the TGFβ pathway in the regulation of α5 β1 integrins by caveolin-1 in human glioblastoma. Int J Cancer. 2012;131(3):601-611.
214. Green DR, Levine B. To be or not to be? How selective autophagy and cell death govern cell fate. Cell. 2014;157(1):65-75.
215. Lau A, Wang XJ, Zhao F, et al. A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol. 2010;30(13):3275-3285.
216. Ichimura Y, Waguri S, Sou YS, et al. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell. 2013;51(5):618-631.
217. Jain A, Lamark T, Sjøttem E, et al. 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. 2010;285(29):22576-22591.
218. Bray K, Mathew R, Lau A, et al. Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. PLoS One. 2012;7(7):e41831.
219. Park SH, Kim JH, Chi GY, et al. Induction of apoptosis and autophagy by sodium selenite in A549 human lung carcinoma cells through generation of reactive oxygen species. Toxicol Lett. 2012;212(3): 252-261.
220. Rao VA, Klein SR, Bonar SJ, et al. The antioxidant transcription factor Nrf2 negatively regulates autophagy and growth arrest induced by the anticancer redox agent mitoquinone. J Biol Chem. 2010;285(45):34447-34459.
221. Zhou Y, Wang HD, Zhu L, et al. Knockdown of Nrf2 enhances autophagy induced by temozolomide in U251 human glioma cell line. Oncol Rep. 2013;29(1):394-400.
222. Li S, Li J, Shen C, et al. tert-Butylhydroquinone (tBHQ) protects hepatocytes against lipotoxicity via inducing autophagy independently of Nrf2 activation. Biochim Biophys Acta. 2014;1841(1): 22-33.
223. Kim TH, Hur EG, Kang SJ, et al. NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1α. Cancer Res. 2011;71(6):2260-2275.
224. Ji X, Wang H, Zhu J, et al. Correlation of Nrf2 and HIF-1α in glioblastoma and their relationships to clinicopathologic features and survival. Neurol Res. 2013;35(10):1044-1050.
225. Ji X, Wang H, Zhu J, et al. Knockdown of Nrf2 suppresses glioblastoma angiogenesis by inhibiting hypoxia-induced activation of HIF-1α. Int J Cancer. 2014;135(3):574-584.
226. Shen H, Yang Y, Xia S, Rao B, Zhang J, Wang J. Blockage of Nrf2 suppresses the migration and invasion of esophageal squamous cell carcinoma cells in hypoxic microenvironment. Dis Esophagus. Epub September 13, 2013.
227. Kwak MK, Kensler T.W. Induction of 26S proteasome subunit PSMB5 by the bifunctional inducer 3-methylcholanthrene through the Nrf2-ARE, but not the AhR/Arnt-XRE, pathway. Biochem Biophys Res Commun. 2006;345(4):1350-1357.
228. Kwak MK, Wakabayashi N, Greenlaw JL, Yamamoto M, Kensler T.W. Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol. 2003;23(23):8786-8794.
229. Schaedler S, Krause J, Himmelsbach K, et al. Hepatitis B virus induces expression of antioxidant response element-regulated genes by activation of Nrf2. J Biol Chem. 2010;285(52):41074-41086.
230. Pickering AM, Linder RA, Zhang H, Forman HJ, Davies K.J. Nrf2-dependent induction of proteasome and Pa28αβ regulator are required for adaptation to oxidative stress. J Biol Chem. 2012;287(13):10021-10031.
231. Höhn TJ, Grune T. The proteasome and the degradation of oxidized proteins: Part III-Redox regulation of the proteasomal system. Redox Biol. 2014;2:388-394.
232. Chen J, Regan R.F. Increasing expression of heme oxygenase-1 by proteasome inhibition protects astrocytes from heme-mediated oxidative injury. Curr Neurovasc Res. 2005;2(3):189-196.
233. Ren S, Smith MJ, Louro ID, et al. The p44S10 locus, encoding a subunit of the proteasome regulatory particle, is amplified during progression of cutaneous malignant melanoma. Oncogene. 2000;19(11):1419-1427.
234. Rho JH, Qin S, Wang JY, Roehrl M.H. Proteomic expression analysis of surgical human colorectal cancer tissues: up-regulation of PSB7, PRDX1, and SRP9 and hypoxic adaptation in cancer. J Proteome Res. 2008;7(7):2959-2972.
235. Hu Z, Pan XF, Wu FQ, et al. Synergy between proteasome inhibitors and imatinib mesylate in chronic myeloid leukemia. PLoS One. 2009;4(7):e6257.
236. Sebens S, Bauer I, Geismann C, et al. Inflammatory macrophages induce Nrf2 transcription factor-dependent proteasome activity in colonic NCM460 cells and thereby confer anti-apoptotic protection. J Biol Chem. 2011;286(47):40911-40921.
237. Du ZX, Yan Y, Zhang HY, et al. Proteasome inhibition induces a p38 MAPK pathway-dependent antiapoptotic program via Nrf2 in thyroid cancer cells. J Clin Endocrinol Metab. 2011;96(5):E763-E771.
238. Ebert B, Kisiela M, Malatkova P, El-Hawari Y, Maser E. Regulation of human carbonyl reductase 3 (CBR3; SDR21C2) expression by Nrf2 in cultured cancer cells. Biochemistry. 2010;49(39): 8499-8511.
239. Kraft DC, Deocaris CC, Wadhwa R, Rattan S.I. Preincubation with the proteasome inhibitor MG-132 enhances proteasome activity via the Nrf2 transcription factor in aging human skin fibroblasts. Ann N Y Acad Sci. 2006;1067:420-424.
240. Rushworth SA, Bowles KM, MacEwan D.J. High basal nuclear levels of Nrf2 in acute myeloid leukemia reduces sensitivity to proteasome inhibitors. Cancer Res. 2011;71(5):1999-2009.
241. Koch A, Steffen J, Krüger E. TCF11 at the crossroads of oxidative stress and the ubiquitin proteasome system. Cell Cycle. 2011;10(8): 1200-1207.
242. Gorowiec MR, Borthwick LA, Parker SM, Kirby JA, Saretzki GC, Fisher A.J. Free radical generation induces epithelial-to-mesenchymal transition in lung epithelium via a TGF-β1-dependent mechanism. Free Radic Biol Med. 2012;52(6):1024-1032.
243. Okita Y, Kamoshida A, Suzuki H, et al. Transforming growth factor-beta induces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene. J Biol Chem. 2013;288(28): 20658-20667.
244. Oh CJ, Kim JY, Choi YK, et al. Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. PLoS One. 2012;7(10):e45870.
245. Choi HK, Pokharel YR, Lim SC, et al. Inhibition of liver fibrosis by solubilized coenzyme Q10: role of Nrf2 activation in inhibiting transforming growth factor-β1 expression. Toxicol Appl Pharmacol. 2009;240(3):377-384.
246. Rachakonda G, Sekhar KR, Jowhar D, et al. Increased cell migration and plasticity in Nrf2-deficient cancer cell lines. Oncogene. 2010;29(25):3703-3714.
247. Pan H, Wang H, Zhu L, Mao L, Qiao L, Su X. The role of Nrf2 in migration and invasion of human glioma cell U251. World Neurosurg. 2013;80(3-4):363-370.
248. Zhang L, Wang N, Zhou S, Ye W, Jing G, Zhang M. Propofol induces proliferation and invasion of gallbladder cancer cells through activation of Nrf2. J Exp Clin Cancer Res. 2012;31:66.
249. Ji XJ, Chen SH, Zhu L, et al. Knockdown of NF-E2-related factor 2 inhibits the proliferation and growth of U251MG human glioma cells in a mouse xenograft model. Oncol Rep. 2013;30(1):157-164.
250. Hanahan D, Weinberg R.A. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
251. Hayes JD, Ashford M.L. Nrf2 orchestrates fuel partitioning for cell proliferation. Cell Metab. 2012;16(2):139-141.
252. Shimizu T, Tolcher AW, Papadopoulos KP, et al. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res. 2012;18(8):2316-2325.
253. Singh A, Happel C, Manna SK, et al. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. J Clin Invest. 2013;123(7):2921-2934.
254. Ma X, Zhang J, Liu S, Huang Y, Chen B, Wang D. Nrf2 knockdown by shRNA inhibits tumor growth and increases efficacy of chemotherapy in cervical cancer. Cancer Chemother Pharmacol. 2012;69(2): 485-494.
255. Jiang T, Chen N, Zhao F, et al. High levels of Nrf2 determine chemoresistance in type II endometrial cancer. Cancer Res. 2010;70(13): 5486-5496.
256. Duong HQ, Yi YW, Kang HJ, et al. Inhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine. Int J Oncol. 2014;44(3):959-969.
257. Akhdar H, Loyer P, Rauch C, Corlu A, Guillouzo A, Morel F. Involvement of Nrf2 activation in resistance to 5-fluorouracil in human colon cancer HT-29 cells. Eur J Cancer. 2009;45(12):2219-2227.
258. Hu XF, Yao J, Gao SG, et al. Nrf2 overexpression predicts prognosis and 5-FU resistance in gastric cancer. Asian Pac J Cancer Prev. 2013;14(9):5231-5235.
259. Gao AM, Ke ZP, Wang JN, Yang JY, Chen SY, Chen H. Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway. Carcinogenesis. 2013;34(8):1806-1814.
260. Singh A, Wu H, Zhang P, Happel C, Ma J, Biswal S. Expression of ABCG2 (BCRP) is regulated by Nrf2 in cancer cells that confers side population and chemoresistance phenotype. Mol Cancer Ther. 2010;9(8):2365-2376.
261. Wang XJ, Li Y, Luo L, et al. Oxaliplatin activates the Keap1/Nrf2 antioxidant system conferring protection against the cytotoxicity of anticancer drugs. Free Radic Biol Med. 2014;70:68-77.
262. Emmink BL, Verheem A, Van Houdt WJ, et al. The secretome of colon cancer stem cells contains drug-metabolizing enzymes. J Proteomics. 2013;91:84-96.
263. Mahaffey CM, Zhang H, Rinna A, Holland W, Mack PC, Forman H.J. Multidrug-resistant protein-3 gene regulation by the transcription factor Nrf2 in human bronchial epithelial and non-small-cell lung carcinoma. Free Radic Biol Med. 2009;46(12):1650-1657.
264. Nishinaka T, Miura T, Okumura M, Nakao F, Nakamura H, Terada T. Regulation of aldo-keto reductase AKR1B10 gene expression: involvement of transcription factor Nrf2. Chem Biol Interact. 2011;191(1-3):185-191.
265. Na HK, Surh Y.J. Oncogenic potential of Nrf2 and its principal target protein heme oxygenase-1. Free Radic Biol Med. 2014;67:353-365.
266. Zhou S, Ye W, Shao Q, Zhang M, Liang J. Nrf2 is a potential therapeutic target in radioresistance in human cancer. Crit Rev Oncol Hematol. 2013;88(3):706-715.
267. Manandhar S, Lee S, Kwak M.K. Effect of stable inhibition of NRF2 on doxorubicin sensitivity in human ovarian carcinoma OV90 cells. Arch Pharm Res. 2010;33(5):717-726.
268. Tan KP, Kosuge K, Yang M, Ito S. NRF2 as a determinant of cellular resistance in retinoic acid cytotoxicity. Free Radic Biol Med. 2008;45(12):1663-1673.
269. Tarumoto T, Nagai T, Ohmine K, et al. Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line. Exp Hematol. 2004;32(4): 375-381.
270. Kweon MH, Adhami VM, Lee JS, Mukhtar H. Constitutive overexpression of Nrf2-dependent heme oxygenase-1 in A549 cells contributes to resistance to apoptosis induced by epigallocatechin 3-gallate. J Biol Chem. 2006;281(44):33761-33772.
271. Limonciel A, Jennings P. A review of the evidence that ochratoxin A is an Nrf2 inhibitor: implications for nephrotoxicity and renal carcinogenicity. Toxins (Basel). 2014;6(1):371-379.
272. Ren D, Villeneuve NF, Jiang T, et al. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci U S.A. 2011;108(4):1433-1438.
273. Cuendet M, Gills JJ, Pezzuto J.M. Brusatol-induced HL-60 cell differentiation involves NF-κB activation. Cancer Lett. 2004;206(1):43-50.
274. Wruck CJ, Claussen M, Fuhrmann G, et al. Luteolin protects rat PC12 and C6 cells against MPP+ induced toxicity via an ERK dependent Keap1-Nrf2-ARE pathway. J Neural Transm Suppl. 2007;(72):57-67.
275. Lin CW, Wu MJ, Liu IY, Su JD, Yen J.H. Neurotrophic and cytoprotective action of luteolin in PC12 cells through ERK-dependent induction of Nrf2-driven HO-1 expression. J Agric Food Chem. 2010;58(7):4477-4486.
276. Pandurangan AK, Ananda Sadagopan SK, Dharmalingam P, Ganapasam S. Luteolin, a bioflavonoid inhibits azoxymethane-induced colorectal cancer through activation of Nrf2 signaling. Toxicol Mech Methods. 2014;24(1):13-20.
277. Lee S, Lim MJ, Kim MH, et al. An effective strategy for increasing the radiosensitivity of human lung cancer cells by blocking Nrf2-dependent antioxidant responses. Free Radic Biol Med. 2012;53(4):807-816.
278. Boettler U, Sommerfeld K, Volz N, et al. Coffee constituents as modulators of Nrf2 nuclear translocation and ARE (EpRE)-dependent gene expression. J Nutr Biochem. 2011;22(5):426-440.
279. van Dijk AE, Olthof MR, Meeuse JC, Seebus E, Heine RJ, van Dam R.M. Acute effects of decaffeinated coffee and the major coffee components chlorogenic acid and trigonelline on glucose tolerance. Diabetes Care. 2009;32(6):1023-1025.
280. Olthof MR, van Dijk AE, Deacon CF, Heine RJ, van Dam R.M. Acute effects of decaffeinated coffee and the major coffee components chlorogenic acid and trigonelline on incretin hormones. Nutr Metab (Lond). 2011;8:10.
281. Zhong Y, Zhang F, Sun Z, et al. Drug resistance associates with activation of Nrf2 in MCF-7/DOX cells, and wogonin reverses it by down-regulating Nrf2-mediated cellular defense response. Mol Carcinog. 2013;52(10):824-834.
282. Sharma PK, Varshney R. 2-Deoxy-D-glucose and 6-aminonicotinamide-mediated Nrf2 down regulation leads to radiosensitization of malignant cells via abrogation of GSH-mediated defense. Free Radic Res. 2012;46(12):1446-1457.