Keap1-Nrf2 signalling in pancreatic cancer

International Journal of Biochemistry and Cell Biology

Volumn 65, Issue , 2015, Pages 288-299

  Hayes, Alastair J ^a   Skouras, Christos ^b   Haugk, Beate ^c   Charnley, Richard M ^d  

^a UNIVERSITY OF EDINBURGH   (United Kingdom)

^b UNIVERSITY OF EDINBURGH   (United Kingdom)

^c ROYAL VICTORIA INFIRMARY   (United Kingdom)

^d FREEMAN HOSPITAL   (United Kingdom)

Author keywords

AKR1B10; Keap1; NQO1; Nrf2; Pancreatic cancer

Indexed keywords

ALDO KETO REDUCTASE FAMILY 1 MEMBER B10; ANTINEOPLASTIC AGENT; BRUSATOL; GLUTATHIONE; HEME OXYGENASE 1; KELCH LIKE ECH ASSOCIATED PROTEIN 1; LUTEOLIN; OXIDOREDUCTASE; PROTEASOME; PROTEIN INHIBITOR; PROTEIN P53; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE DEHYDROGENASE (UBIQUINONE); THIOREDOXIN; THIOREDOXIN REDUCTASE 1; TRANSCRIPTION FACTOR NRF2; TRANSCRIPTION FACTOR NRF2 INHIBITOR; TRIGONELLINE; TUMOR PROTEIN 53 INCUDED PROTEIN; UNCLASSIFIED DRUG; XENOBIOTIC AGENT; KEAP1 PROTEIN, HUMAN; SIGNAL PEPTIDE;

ANTIOXIDANT RESPONSIVE ELEMENT; CARCINOGENESIS; CELL DAMAGE; CELL PROTECTION; CELL STRESS; CELL SURVIVAL; CELL VIABILITY; CHEMOSENSITIVITY; CYTOSKELETON; DNA SEQUENCE; DOWN REGULATION; DRUG DETOXIFICATION; GENE EXPRESSION; GENE MUTATION; HUMAN; METABOLISM; NONHUMAN; OXIDATIVE STRESS; PANCREAS CANCER; PROTEIN EXPRESSION; PROTEIN FUNCTION; REDOX STRESS; REVIEW; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; UPREGULATION; ANIMAL; GENETICS; PANCREAS CARCINOMA; PANCREAS TUMOR;

ANIMALS; CARCINOMA, PANCREATIC DUCTAL; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; NF-E2-RELATED FACTOR 2; PANCREATIC NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 84936934546     PISSN: 13572725     EISSN: 18785875     Source Type: Journal    
DOI: 10.1016/j.biocel.2015.06.017     Document Type: Review

References (135)

1. A. Acharya, I. Das, D. Chandhok, and T. Saha Redox regulation in cancer: a double-edged sword with therapeutic potential Oxid. Med. Cell. Longev. 3 1 2010 23 34
2. A.S. Agyeman, R. Chaerkady, P.G. Shaw, N.E. Davidson, K. Visvanathan, A. Pandey, and T.W. Kensler Transriptomic and proteomic profiling of KEAP1 disrupted and sulphoraphane-treated human breast epithelial cells reveals common expression profiles Breast Cancer Res. Treat. 132 1 2012 175 187
3. T. Al Saati, P. Clerc, N. Hanoun, S. Peuget, H. Lulka, V. Gigoux, F. Capilla, B. Béluchon, A. Couvelard, J. Selves, L. Buscall, A. Carrier, N. Dusetti, and M. Dufresne Oxidative stress induced by inactivation of TP53INP1 cooperates with KrasG12D to initiate and promote pancreatic carcinogenesis in the murine pancreas Am. J. Pathol. 182 6 2013 1996 2004
4. E. Altomare, I. Grattagliano, G. Vendemiale, V. Palmieri, and G. Palasciano Acute ethanol administration induces oxidative changes in rat pancreatic tissue Gut 38 5 1996 742 745
5. A. Arlt, I. Bauer, C. Schafmayer, J. Tepel, S.S. Müerköster, M. Brosch, C. Röder, H. Kalthoff, J. Hampe, M.P. Moyer, U.R. Fölsch, and H. Scha¨fer Increased proteasome subunit protein expression and proteasome activity in colon cancer relate to an enhanced activation of nuclear factor E2-relate factor 2 (Nrf2) Oncogene 28 45 2009 3983 3996
6. A. Arlt, S. Sebens, S. Krebs, C. Geismann, M. Grossmann, M.L. Kruse, S. Schreiber, and H. Scha¨fer Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity Oncogene 32 40 2013 4825 4835
7. E.S. Arnér, and A. Holmgren The thioredoxin system in cancer Semin. Cancer Biol. 16 6 2006 420 426
8. N.B. Arnold, K. Ketterer, J. Kleeff, H. Friess, M.W. Buchler, and M. Korc Thioredoxin is downstream of Smad7 in a pathway that promotes growth and suppresses cisplatin-induced apoptosis in pancreatic cancer Cancer Res. 64 10 2004 3599 3606
9. N.S. Awadallah, D. Dehn, R.J. Shah, S. Russell Nash, Y.K. Chen, D. Ross, J.S. Bentz, and K.R. Shroyer NQO1 expression in pancreatic cancer and its potential use as a biomarker Appl. Immunohistochem. Mol. Morphol. 16 1 2008 24 31
10. E. Bagli, M. Stefaniotou, L. Morbidelli, M. Ziche, K. Psillas, C. Murphy, and T. Fotsis Luteolin inhibits vascular endothelial growth factor-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 3′-kinase activity Cancer Res. 64 21 2004 7936 7946
11. H. Bai, H. Li, W. Zhang, K.A. Matkowskyj, J. Liao, S.K. Srivastava, and G.Y. Yang Inhibition of chronic pancreatitis and pancreatic intraepithelial neoplasia (PanIN) by capsaicin in LSL-KrasG12D/Pdx1-Cre mice Carcinogenesis 32 11 2011 1689 1696
12. P.O. Berberat, Z. Dambrauskas, A. Gulbinas, T. Giese, N. Giese, B. Künzli, F. Autschbach, S. Meuer, M.W. Büchler, and H. Friess Inhibition of heme oxygenase-1 increases responsiveness of pancreatic cancer cells to anti-cancer treatment Clin. Cancer Res. 11 10 2005 3790 3798
13. L. Baird, D. Lleres, S. Swift, and A.T. Dinkova-Kostova Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex Proc. Natl. Acad. Sci. U. S. A. 110 38 2013 15259 15264
14. G. Berrozpe, J. Schaeffer, M.A. Peinado, F.X. Real, and M. Perucho Comparative analysis of mutations in the p53 and K-ras genes in pancreatic cancer Int. J. Cancer 58 2 1994 185 191
15. U. Boettler, K. Sommerfeld, N. Volz, G. Pahlke, N. Teller, V. Somoza, R. Lang, T. Hofmann, and D. Marko Coffee constituents as modulators of Nrf2 nuclear translocation and ARE (EpRE)-dependent gene expression J. Nutr. Biochem. 22 5 2011 424 440
16. C.E. Cano, J. Gommeaux, S. Pietri, M. Culcasi, S. Garcia, M. Seux, S. Barelier, S. Vasseur, R.P. Spoto, M.J. Pébusque, N.J. Dusetti, J.L. Iovanna, and A. Carrier Tumor protein 53-induced nuclear protein 1 is a major mediator of p53 antioxidant function Cancer Res. 69 1 2009 219 226
17. X. Cai, W. Lu, T. Ye, M. Lu, J. Wang, J. Huo, S. Qian, X. Wang, and P. Cao The molecular mechanism of luteolin-induced apoptosis is potentially related to inhibition of angiogenesis in human pancreatic carcinoma cells Oncol. Rep. 28 4 2012 1353 1361
18. M. Cebula, E.E. Schmidt, and E.S. Arnér TrxR1 as a potent regulator of the Nrf2-Keap1 response system Antioxid. Redox Signal. 2015 (Epub ahead of print)
19. D.K. Chang, S.M. Grimmond, and A.V. Biankin Pancreatic cancer genomics Curr. Opin. Genet. Dev. 24 2014 74 81
20. S.J. Chapple, R.C.M. Siow, and G.E. Mann Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging Int. J. Biochem. Cell Biol. 44 8 2012 1315 1320
21. N. Chen, X. Yi, N. Abushahin, S. Pang, D. Zhang, B. Kong, and W. Zheng Nrf2 expression in endometrial serous carcinomas and its precancers Int. J. Clin. Exp. Pathol. 4 1 2010 85 96
22. S. Chowdhry, Y. Zhang, M. McMahon, C. Sutherland, A. Cuadrado, and J.D. Hayes 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 32 2013 3765 3781
23. Y.T. Chung, K.A. Matkowskyj, H. Li, H. Bai, W. Zhang, M.S. Tsao, J. Liao, and G.Y. Yang Overexpression and oncogenic function of aldo-keto reductase family 1B10 (AKR1B10) in pancreatic carcinoma Mod. Pathol. 25 5 2012 758 766
24. X. Cia, W. Lu, T. Ye, M. Lu, J. Wang, J. Huo, S. Qian, X. Wang, and P. Cao The molecular mechanism of luteolin-induced apoptosis is potentially related to inhibition of angiogenesis in human pancreatic carcinoma cells Oncol. Rep. 28 4 2012 1353 1361
25. I.M. Copple The Keap1-Nrf2 cell defence pathway - a promising therapeutic target? Adv. Pharmacol. 63 2012 43 79
26. J.J. Cullen, M.M. Hinkhouse, M. Grady, A.W. Gaut, J. Liu, Y.P. Zhang, C.J. Weydert, F.E. Domann, and L.W. Oberley Dicumarol inhibition of NADPH:quinone oxidoreductase induces growth inhibition of pancreatic cancer via a superoxide-mediated mechanism Cancer Res. 63 17 2003 5513 5520
27. S.B. Cullinan, and J.A. Diehl PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum J. Biol. Chem. 279 19 2004 20108 20117
28. S.B. Cullinan, D. Zhang, M. Hannink, E. Arvisais, R.J. Kaufman, and J.A. Diehl Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival Mol. Cell. Biol. 23 20 2003 7198 7209
29. D.L. Dehn, D. Siegel, K.S. Zafar, P. Reigan, E. Swann, C.J. Moody, and D. Ross 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, exhibits activity against human pancreatic cancer in vitro and in vivo Mol. Cancer Ther. 5 7 2006 1702 1709
30. G.M. DeNicola, F.A. Karreth, T.J. Humpton, A. Gopinathan, C. Wei, K. Frese, D. Mangal, K.H. Yu, C.J. Yeo, E.S. Calhoun, F. Scrimieri, J.M. Winter, R.H. Hruban, C. lacobuzio-Donahue, S.E. Kern, I.A. Blair, and D.A. Tuveson Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis Nature 475 7354 2011 106 109
31. T.W. Devling, C.D. Lindsay, L.I. McLellan, M. McMahon, and J.D. Hayes Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype Proc. Natl. Acad. Sci. U. S. A. 102 20 2005 7280 7285
32. L.L. Dunn, R.G. Midwinter, J. Ni, H.A. Hamid, C.R. Parish, and R. Stoker New insights into intracellular locations and functions of heme oxygenase-1 Antioxid. Redox Signal. 20 11 2014 1723 1742
33. H.Q. Duong, Y.W. Yi, H.J. Kang, Y.B. Hong, W. Tang, A. Wang, Y.S. Seong, and I. Bae Inhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine Int. J. Oncol. 44 3 2014 959 969
34. G. Eades, M. Yang, Y. Yao, Y. Zhang, and Q. Zhou miR-200a regulates Nrf2 activation by targeting Keap1 mRNA in breast cancer cells J. Biol. Chem. 286 47 2011 40725 40733
35. S. Fourquet, R. Guerois, D. Biard, and M.B. Toledano Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation J. Biol. Chem. 285 11 2010 8463 8471
36. J. Fredebohm, M. Boettcher, C. Eisen, M.M. Gaida, A. Heller, S. Keleg, J. Tost, K.M. Greulich-Bode, A. Hotz-Wagenblatt, M. Lathrop, N.A. Giese, and J.D. Hoheisel Establishment and characterization of a highly tumourigenic and cancer stem cell enriched pancreatic cancer cell line as a well defined model system PLoS ONE 7 11 2012 e48503
37. P.C. Ganesh, Sreejayan, and M.N. Rao Evidence for oxidant stress in chronic pancreatitis Indian J. Gastroenterol. 18 4 1999 156 157
38. M. Gironella, M. Seux, M.J. Xie, C. Cano, R. Tomasini, J. Gommeaux, S. Garcia, J. Nowak, M.L. Yeung, K.T. Jeang, A. Chaix, L. Fazli, Y. Motoo, Q. Wang, P. Rocchi, A. Russo, M. Gleave, J.C. Dagorn, J.L. Iovanna, A. Carrier, M.J. Pébusque, and N.J. Dusetti Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155 and its restoration inhibits tumour development Proc. Natl. Acad. Sci. U. S. A. 104 41 2007 16170 16175
39. C. Guerra, A.J. Schuhmacher, M. Cañamero, P.J. Grippo, L. Verdaguer, L. Pérez-Gallego, P. Dubus, E.P. Sandgren, and M. Barbacid Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice Cancer Cell 11 3 2007 291 302
40. B. Halliwell, and J.M.C. Gutteridge Free Radicals in Biology and Medicine 4th ed. 2007 Oxford University Press
41. D. Hanahan, and R.A. Weinberg Hallmarks of cancer: the next generation Cell 144 5 2011 646 674
42. J.D. Hayes, S.A. Chanas, C.J. Henderson, M. McMahon, C. Sun, G.J. Moffat, C.R. Wolf, and M. Yamamoto The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin Biochem. Soc. Trans. 28 2 2000 33 41
43. J.D. Hayes, M.O. Kelleher, and I.M. Eggleston The cancer chemopreventive actions of phytochemicals derived from glucosinolates Eur. J. Nutr. 47 Suppl. 2 2008 73 88
44. J.D. Hayes, and M. McMahon NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer Trends Biochem. Sci. 34 4 2009 176 188
45. J.D. Hayes, and A.T. Dinkova-Kostova The Nrf2 regulatory network provides an interface between redox and intermediary metabolism Trends Biochem. Sci. 39 4 2014 199 218
46. L.G. Higgins, M.O. Kelleher, I.M. Eggleston, K. Itoh, M. Yamamoto, and J.D. Hayes Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents Toxicol. Appl. Pharmacol. 237 3 2009 267 280
47. S. Homma, Y. Ishii, Y. Morishima, T. Yamadori, Y. Matsuno, N. Haraguchi, N. Kikuchi, H. Satoh, T. Sakamoto, N. Hizawa, K. Itoh, and M. Yamamoto Nrf2 enhances cell proliferation and resistance to anti-cancer drugs in human lung cancer Clin. Cancer Res. 15 10 2009 3423 3432
48. Y.B. Hong, H.J. Kang, S.Y. Kwon, H.J. Kim, K.Y. Kwon, C.H. Cho, J.M. Lee, B.V. Kallakury, and I. Bae Nuclear factor (erythroid-derived 2)-like 2 regulates drug resistance in pancreatic cancer cells Pancreas 39 4 2010 463 472
49. J.M. Hourihan, J.G. Kenna, and J.D. Hayes The gasotransmitter hydrogen sulfide induces Nrf2-target genes by inactivating the keap1 ubiquitin ligase substrate adaptor through formation of a disulfide bond between cys-226 and cys-613 Antioxid. Redox Signal. 19 5 2013 465 481
50. Y. Ino, R. Yamazaki-Itoh, K. Shimada, M. Iwasaki, T. Kosuge, Y. Kanai, and N. Hiraoka Immune cell infiltrate as an indicator of the immune microenvironment of pancreatic cancer Br. J. Cancer 108 4 2013 914 923
51. K. Itoh, T. Chiba, S. Takahashi, T. Ishii, K. Igarashi, Y. Katoh, T. Oyake, N. Hayashi, K. Satoh, I. Hatayama, M. Yamamoto, and Y. Nabeshima An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements Biochem. Biophys. Res. Commun. 236 2 1997 313 322
52. K. Itoh, N. Wakabayashi, Y. Katoh, T. Ishii, K. Igarashi, J.D. Engel, and M. Yamamoto Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain Genes Dev. 13 1 1999 76 86
53. K. Itoh, N. Wakabayashi, Y. Katoh, T. Ishii, T. O'Connor, and M. Yamamoto Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles Genes Cells 8 4 2003 379 391
54. S. Jang, K. Kelly, and R.W. Johnson Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1 Proc. Natl. Acad. Sci. U. S. A. 105 21 2008 7534 7539
55. J.L. Johnson, and E. Gonsalez de Mejia Interactions between dietary flavonoids apigenin or luteolin and chemotherapeutic drugs to potentiate anti-proliferative effect on human pancreatic cancer cells, in vitro Food Chem. Toxicol. 60 2013 83 91
56. J.L. Johnson, V.P. Dia, M. Wallig, and E. Gonzalez de Mejia Luteolin and gemcitabine protect against pancreatic cancer in an orthotopic mouse model Pancreas 44 1 2015 144 151
57. S. Jones, X. Zhang, D.W. Parsons, and et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses Science 321 5897 2008 1801 1806
58. H.Q. Ju, T. Gocho, M. Aguilar, M. Wu, Z.N. Zhuang, J. Fu, K. Yanaga, P. Huang, and P.J. Chiao Mechanisms of overcoming intrinsic resistance to in pancreatic ductal adenocarcinoma through the redox modulation Mol. Cancer Ther. 14 3 2015 788 798
59. Y. Kim, D. Han, H. Min, J. Jin, E.C. Yi, and Y. Kim Comparative proteomic profiling of pancreatic ductal adenocarcinoma cell lines Mol. Cells 37 12 2014 888 898
60. B. Kong, C. Qia, M. Erkan, J. Kleeff, and C.W. Michalski Overview on how oncogenic Kras promotes pancreatic carcinogenesis by inducing low intracellular ROS levels Front. Physiol. 12 4 2013 246
61. M.K. Kwak, N. Wakabayashi, J.L. Greenlaw, M. Yamamoto, and T.W. Kensler Antioxidants enhance mammalian proteasome expression through Keap1-Nrf2 signaling pathway Mol. Cell. Biol. 23 23 2003 8786 8794
62. A. Lau, N.F. Villeneuve, Z. Sun, P.K. Wong, and D.D. Zhang Dual roles of Nrf2 in cancer Pharmacol. Res. 58 5-6 2008 262 270
63. M. Lesina, M.U. Kurkowski, K. Ludes, S. Rose-John, M. Treiber, G. Klöppel, A. Yoshimura, W. Reindl, B. Sipos, S. Akira, R.M. Schmid, and H. Algül Stat3/Socs3 activation by IL-6 transsignalling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer Cancer Cell 19 4 2011 456 469
64. A. Lewis, M. Ough, L. Li, M.M. Hinkhouse, J.M. Ritchie, D.R. Spitz, and J.J. Cullen Treatment of pancreatic cancer cells with dicumarol induces cytotoxicity and oxidative stress Clin. Cancer Res. 10 13 2004 4550 4558
65. A.M. Lewis, M. Ough, M.M. Hinkhouse, M.S. Tsao, L.W. Oberley, and J.J. Cullen Targeting NAD(P)H:quinone oxidoreductase (NQO1) in pancreatic cancer Mol. Carcinog. 43 4 2005 215 224
66. H. Li, A.L. Yang, Y.T. Chung, W. Zhang, J. Liao, and G.Y. Yang Sulindac inhibits pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice via suppressing aldo-keto reductase family 1B10 (AKR1B10) Carcinogenesis 34 9 2013 2090 2098
67. L.S. Li, E.A. Bey, Y. Dong, J. Meng, B. Patra, J. Yan, X.J. Xie, R.A. Brekken, C.C. Barnett, W.G. Bornmann, J. Gao, and D.A. Boothman Modulating endogenous NQO1 levels identifies key regulatory mechanisms of action of ß-lapachone for pancreatic cancer therapy Clin. Cancer Res. 17 2 2011 275 285
68. A. Lister, T. Nedjadi, N.R. Kitteringham, F. Campbell, E. Costello, B. Lloyd, I.M. Copple, S. Williams, A. Owen, J.P. Neoptolemos, C.E. Goldring, and B.K. Park Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy Mol. Cancer 10 2011 37
69. C.D. Logsdon, D.M. Simeone, C. Binkley, T. Arumugam, J.K. Greenson, T.J. Giordano, D.E. Misek, R. Kuick, and S. Hanash Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer Cancer Res. 63 10 2003 2649 2657
70. C.D. Logsdon, and B. Ji The role of protein synthesis and digestive enzymes in acinar cell injury Nat. Rev. Gastroenterol. Hepatol. 10 6 2013 362 370
71. M. López-Lázaro Distribution and biological activities of the flavonoid luteolin Mini Rev. Med. Chem. 9 1 2009 31 59
72. P. Loukopoulos, K. Kanetaka, M. Takamura, T. Shibata, M. Sakamoto, and S. Hirohashi Orthotopic transplantation models of pancreatic adenocarcinoma derived from cell lines and primary tumors and displaying varying metastatic activity Pancreas 29 3 2004 193 203
73. J. Lu, and A. Holmgren The thioredoxin antioxidant system Free Radic. Biol. Med. 66 2014 75 87
74. B.D. Lyn-Cook, Y. Yan-Sanders, S. Moore, S. Taylor, B. Word, and G.J. Hammons Increased levels of NAD(P)H:quinone oxidoreductase 1 (NQO1) in pancreatic tissues from smokers and pancreatic adenocarcinomas: a potential biomarker of early damage in the pancreas Cell Biol. Toxicol. 22 2 2006 73 80
75. M. McMahon, K. Itoh, M. Yamamoto, and J.D. Hayes Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression J. Biol. Chem. 278 24 2003 21592 21600
76. M. McMahon, N. Thomas, K. Itoh, M. Yamamoto, and J.D. Hayes Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a "tethering" mechanism: a two-site interaction model for the Nrf2-Keap1 complex J. Biol. Chem. 281 34 2006 24756 24768
77. G.K. McWalter, L.G. Higgins, L.I. McLellan, C.J. Henderson, L. Song, P.J. Thornalley, K. Itoh, M. Yamamoto, and J.D. Hayes Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates J. Nutr. 134 Suppl. 12 2004 3499S 3506S
78. P.J. Meakin, S. Chowdhry, R.S. Sharma, F.B. Ashford, S.V. Walsh, R.J. McCrimmon, A.T. Dinkova-Kostova, J.F. Dillion, J.D. Hayes, and M.L. Ashford Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance Mol. Cell. Biol. 34 17 2014 3305 3320
79. Y. Mitsuishi, K. Taguchi, Y. Kawatani, T. Shibata, T. Nukiwa, H. Aburatani, M. Yamamoto, and H. Motohashi Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprograming Cancer Cell 22 1 2012 66 79
80. B. Mohelnikova-Duchonova, V. Brynychova, M. Oliverius, E. Honsova, Z. Kala, K. Muckova, and P. Soucek Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonmalignant tissues Pancreas 42 4 2013 707 716
81. P.S. Moore, B. Sipos, S. Orlandini, C. Sorio, F.X. Real, N.R. Lemoine, T. Gress, C. Bassi, G. Klöppel, H. Kalthoff, H. Ungefroren, M. Löhr, and A. Scarpa Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4 Virchows Arch. 439 6 2001 798 802
82. H. Motohashi, and M. Yamamoto Nrf2-Keap1 defines a physiologically important stress response mechanism Trends Mol. Med. 10 11 2004 549 557
83. L.A. Muscarella, P. Parrella, V. D'Alessandro, A. la Torre, R. Barbano, A. Fontana, A. Tancredi, V. Guarnieri, T. Balsamo, M. Coco, M. Copetti, F. Pellegrini, P. De Bonis, M. Bisceglia, G. Scaramuzzi, E. Maiello, V.M. Valori, G. Merla, G. Vendemiale, and V.M. Fazio Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer Epigenetics 6 6 2011 710 719
84. M. Naumann, N. Savitskaia, C. Eilert, A. Schramm, H. Kalthoff, and W. Schmiegel Frequent codeletion of p16/MTS1 and p15/MTS2 and genetic alterations in p16/MTS1 in pancreatic tumors Gastroenterology 110 4 1996 1215 1224
85. P. Nioi, and J.D. Hayes Contribution of NAD(P)H:quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loop-helix transcription factors Mutat. Res. 555 1-2 2004 v149 v171
86. K.A. Nolan, H. Zhao, P.F. Faulder, A.D. Frenkel, D.J. Timson, D. Siegel, D. Ross, T.R. Burke Jr., I.J. Stratford, and R.A. Bryce Coumarin-based inhibitors of human NAD(P)H:quinone oxidoreductase-1. Identification, structure-activity, off-target effects and in vitro human pancreatic cancer toxicity J. Med. Chem. 50 25 2007 6316 6325
87. K.J. O'Byrne, and A.G. Dalgleish Chronic immune activation and inflammation as the cause of malignancy Br. J. Cancer 85 4 2001 473 483
88. A. Olayanju, I.M. Copple, H.K. Bryan, G.T. Edge, R.L. Sison, M.W. Wong, Z.Q. Lai, Z.X. Lin, K. Dunn, C.M. Sanderson, A.F. Alghanem, M.J. Cross, E.C. Ellis, M. Ingelman-Sundberg, H.Z. Malik, N.R. Kitteringham, C.E. Goldring, and B.K. Park Brusatol provokes a rapid and transient inhibition of Nrf2 signalling and sensitizes mammalian cells to chemical toxicity - implications for therapeutic targeting of Nrf2 Free Radic. Biol. Med. 78 2015 202 212
89. M. Ough, A. Lewis, E.A. Bey, J. Gao, J.M. Ritchie, W. Bornmann, D.A. Boothman, L.W. Oberley, and J.J. Cullen Efficacy of beta-lapachone in pancreatic cancer treatment: exploiting the novel, therapeutic target NQO1 Cancer Biol. Ther. 4 1 2005 95 102
90. B. Padmanabhan, K.I. Tong, T. Ohta, Y. Nakamura, M. Scharlock, M. Ohtsuji, M.I. Kang, A. Kobayashi, S. Yokoyama, and M. Yamamoto Mol. Cell 21 5 2006 689 700
91. G. Powis, and W.R. Montfort Properties and biological activities of thioredoxins Annu. Rev. Pharmacol. Toxicol. 41 2001 261 295
92. P. Rada, A.I. Rojo, S. Chowdhry, M. McMahon, J.D. Hayes, and A. Cuadrado SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner Mol. Cell. Biol. 31 6 2011 1121 1133
93. R.K. Ramanathan, J. Abbruzzese, T. Dragovich, L. Kirkpatrick, J.M. Guillen, A.F. Baker, L.A. Pestano, S. Green, and D.D. Von Hoff A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after gemcitabine-containing combination Cancer Chemother. Pharmacol. 67 3 2011 503 509
94. P. Reigan, M.A. Colucci, D. Siegel, A. Chilloux, C.J. Moody, and D. Ross Development of indolequinone mechanism-based inhibitors of NAD(P)H:quinone oxidoreductase 1 (NQO1): NQO1 inhibition and growth inhibitory activity in human pancreatic MIA PaCa-2 cancer cells Biochemistry 46 20 2007 5941 5950
95. D. Ren, N.F. Villeneuve, T. Jiang, T. Wu, A. Lau, H.A. Toppin, and D.D. Zhang Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defence mechanism Proc. Natl. Acad. Sci. U. S. A. 108 4 2011 1433 1438
96. J.A. Rivera, C.J. Rall, F. Graeme-Cook, C. Fernández-del Castillo, P. Shu, N. Lakey, R. Tepper, D.W. Rattner, A.L. Warshaw, and A.K. Rustgi Analysis of Kras oncogene mutations in CP with ductal hyperplasia Surgery 121 1 1997 42 49
97. D. Ross, J.K. Kepa, S.L. Winski, H.D. Beall, A. Anwar, and D. Siegel NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms Chem. Biol. Interact. 129 1-2 2000 77 79
98. B. Rotblat, G. Melino, and R.A. Knight NRF2 and p53: Januses in cancer? Oncotarget 3 11 2012 1272 1283
99. S.W. Ryter, J. Alam, and A.M. Choi Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications Physiol. Rev. 86 2 2006 583 650
100. R.P. Sah, S.K. Garg, A.K. Dixit, V. Dudeja, R.K. Dawra, and A.K. Saluja Endoplasmic reticulum stress is chronically activated in chronic pancreatitis J. Biol. Chem. 289 40 2014 27551 27561
101. H. Satoh, T. Moriguchi, K. Taguchi, J. Takai, J.M. Maher, T. Suzuki, P.T. Winnard Jr., V. Raman, M. Ebina, T. Nukiwa, and M. Yamamoto Nrf2-deficiency creates a responsive microenvironment for metastais to the lung Carcinogenesis 31 2010 1833 1843
102. K. Selvendiran, H. Koga, T. Ueno, T. Yoshida, M. Maeyama, T. Torimura, H. Yano, M. Kojiro, and M. Sata Luteolin promotes degradation in signal transducer and activator of transcription 3 in human hepatoma cells: an implication for the antitumor potential of flavonoids Cancer Res. 66 9 2006 4826 4834
103. T. Shibata, A. Kokubu, M. Gotoh, H. Ojima, T. Ohta, M. Yamamoto, and S. Hirohashi Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer Gastroenterology 135 4 2008 1358 1368
104. D. Siegel, J.K. Kepa, and D. Ross NAD(P)H:quinone oxidoreductase 1 (NQO1) localizes to the mitotic spindle in human cells PLoS ONE 7 9 2012 e44861
105. A. Singh, V. Misra, R.K. Thimmulappa, H. Lee, S. Ames, M.O. Hoque, J.G. Herman, S.B. Baylin, D. Sidransky, E. Gabrielson, M.V. Brock, and S. Biswal Dysfunctional Keap1-NRF2 interaction in non-small-cell lung cancer PLoS Med. 3 10 2006 e420
106. S. Singh, J. Arcaroli, D.C. Thompson, W. Messermith, and V. Vasiliou Acetaldehyde and retinaldehyde-metabolizing enzymes in colon and pancreatic cancers Adv. Exp. Med. Biol. 815 2015 281 294
107. Y. Soini, M. Eskelinen, P. Juvonen, V. Ka¨rja¨, K.M. Haapasaari, A. Saarela, and P. Karihtala Nuclear Nrf2 expression is related to a poor survival in pancreatic adenocarcinoma Pathol. Res. Pract. 210 1 2014 35 39
108. T. Stevens, M.P. Berk, R. Lopez, Y.M. Chung, R. Zhang, M.A. Parsi, M.P. Bronner, and A.E. Feldstein Lipidomic profiling of serum and pancreatic fluid in chronic pancreatitis Pancreas 41 4 2012 518 522
109. T. Suzuki, T. Shibata, K. Takaya, K. Shiraishi, T. Kohno, H. Kunitoh, K. Tsuta, K. Furuta, K. Goto, F. Hosoda, H. Sakamoto, H. Motohashi, and M. Yamamoto Regulatory nexus of synthesis and degradation deciphers cellular Nrf2 expression levels Mol. Cell. Biol. 33 12 2013 2402 2412
110. K. Taguchi, N. Fujikawa, M. Komatsu, T. Ishii, M. Unno, T. Akaike, H. Motohashi, and M. Yamamoto Keap1 degradation by autophagy for the maintenance of redox homeostasis Proc. Natl. Acad. Sci. U. S. A. 109 34 2012 13561 13566
111. X. Tang, H. Wang, L. Fan, X. Wu, A. Xin, H. Ren, and X.J. Wang Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs Free Radic. Biol. Med. 50 11 2011 1599 1609
112. J.F. Turrens Mitochondrial formation of reactive oxygen species J. Physiol. 15 552 2003 335 344
113. M. Valenzuela, C. Glorieux, J. Stockis, B. Sid, J.M. Sandoval, K.B. Felipe, M.R. Kviecinski, J. Verrax, and P. Buc Calderon Retinoic acid synergizes ATO-mediated cytotoxicity by precluding Nrf2 activity in AML cells Br. J. Cancer 111 5 2014 874 882
114. N. Wakabayashi, K. Itoh, J. Wakabayashi, H. Motohashi, S. Noda, S. Takahashi, S. Imakado, T. Kotsuji, F. Otsuka, D.R. Roop, T. Harada, J.D. Engel, and M. Yamamoto Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation Nat. Genet. 35 3 2003 238 245
115. N. Wakabayashi, A.T. Dinkova-Kostova, W.D. Holtzclaw, M.I. Kang, A. Kobayashi, M. Yamamoto, T.W. Kensler, and P. Talalay Protection against electrophile and oxidant stress by induction of the phase 2 response; fate of cysteines of the Keap1 sensor modified by inducers Proc. Natl. Acad. Sci. U. S. A. 101 7 2004 2040 2045
116. R. Wang, J. An, F. Ji, H. Jiao, H. Sun, and D. Zhou Hypermethylation of the Keap1 gene in human lung cancer cell lines and lung cancer tissues Biochem. Biophys. Res. Commun. 373 1 2008 151 154
117. X.J. Wang, J.D. Hayes, C.J. Henderson, and C.R. Wolf 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 49 2007 19589 19594
118. F. Weinberg, R. Hamanaka, W.W. Wheaton, S. Weinberg, J. Joseph, M. Lopez, B. Kalyanaraman, G.M. Mutlu, G.R. Budinger, and N.S. Chandel Mitochondrial metabolism and ROS generation are essential for K-ras mediated tumorigenicity Proc. Natl. Acad. Sci. U. S. A. 107 19 2010 8788 8793
119. U. Wenzel, S. Kuntz, M.D. Brendel, and H. Daniel Dietary flavone is a potent apoptosis inducer in human colon carcinoma cells Cancer Res. 60 14 2000 3823 3831
120. D.C. Whitcomb, Inflammation, and V. Cancer Chronic pancreatitis and pancreatic cancer Am. J. Physiol. Gastrointest. Liver Physiol. 287 2 2004 G315 G319
121. R. Yan, X. Zu, J. Ma, Z. Liu, M. Adeyanju, and D. Cao Aldo-keto reductase family 1 B10 gene silencing results in growth inhibition of colorectal cancer cells: implication for cancer intervention Int. J. Cancer 121 10 2007 2301 2306
122. C. Yan, B. Shieh, P. Reigan, Z. Zhang, M.A. Colucci, A. Chilloux, J.J. Newsome, D. Siegel, D. Chan, C.J. Moody, and D. Ross Potent activity of indolequinones against human pancreatic cancer: identification of thioredoxin reductase as a potential target Mol. Pharmacol. 76 2009 163 172
123. C. Yan, D. Siegel, J. Newsome, A. Chilloux, C.J. Moody, and D. Ross Antitumor indolequinones induced apoptosis in human pancreatitic cancer cells via inhibition of thioredoxin reductase and activation of redox signalling Mol. Pharmacol. 81 3 2012 401 410
124. L. Yang, J. Shen, S. He, G. Hu, J. Shen, F. Wang, L. Xu, W. Dai, J. Xiong, J. Ni, C. Guo, R. Wan, and X. Wang L-cysteine administration attenuates pancreatic fibrosis induced by TNBS in rats inhibiting the activation of pancreatic stellate cells PLoS ONE 7 2 2012 e31807
125. Y.W. Yi, and S. Oh Comparative analysis of Nrf2-responsive gene expression in AcPC-1 pancreatic cancer cell line Gene Genomics 37 2015 97 109
126. S. Yu, T.O. Khor, K.L. Cheung, W. Li, T.Y. Wu, Y. Huang, B.A. Foster, Y.W. Kan, and A.N. Kong Nrf2 expression is regulated by epigenetic mechanisms in prostate cancer of TRAMP mice PLoS ONE 5 1 2010 e8579
127. S. Zeki, S. Miura, H. Suzuki, N. Watanabe, M. Adachi, H. Yokoyama, Y. Horie, H. Saito, S. Kato, and H. Ishii Xanthine oxidase-derived oxygen radicals play significant roles in the development of chronic pancreatitis in WBN/Kob rats J. Gastroenterol. Hepatol. 17 5 2002 606 616
128. D.D. Zhang Mechanistic studies of the Nrf2-Keap1 signaling pathway Drug Metab. Rev. 38 4 2006 769 789
129. D.D. Zhang, and M. Hannink Distinct cystein residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 for stabilization of Nrf2 by chemopreventive agents and oxidative stress Mol. Cell. Biol. 23 22 2003 8137 8151
130. D.D. Zhang, S.C. Lo, J.V. Cross, D.J. Templeton, and M. Hannink Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex Mol. Cell. Biol. 24 24 2004 10941 10953
131. K. Zhang, and R.J. Kaufman From endoplasmic-reticulum stress to the inflammatory response Nature 454 7203 2008 455 462
132. P. Zhang, A. Singh, S. Yegnasubramanian, D. Esopi, P. Kombairaju, M. Bodas, H. Wu, S.G. Bova, and S. Biswal 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 2 2010 336 346
133. W. Zhang, H. Li, Y. Yang, J. Liao, and G.Y. Yang Knockdown or inhibition of aldo-keto reductase 1B10 inhibits pancreatic carcinoma growth via modulating Kras-E-cadherin pathway Cancer Lett. 355 2 2014 273 280
134. Y. Zhang, W. Yan, M.A. Collins, F. Bednar, S. Rakshit, B.R. Zetter, B.Z. Stanger, I. Chung, A.D. Rhim, and M.P. di Magliano Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signalling activation and oxidative stress resistance Cancer Res. 73 20 2013 6359 6374
135. L.M. Zipper, and R.T. Mulcahy Inhibition of ERK and p38 MAP kinases inhibits binding of Nrf2 and induction of GCS genes Biochem. Biophys. Res. Commun. 278 2 2000 484 492