Withaferin A induces Nrf2-dependent protection against liver injury: Role of Keap1-independent mechanisms

Free Radical Biology and Medicine

Volumn 101, Issue , 2016, Pages 116-128

  Palliyaguru, Dushani L ^a   Chartoumpekis, Dionysios V ^b   Wakabayashi, Nobunao ^b   Skoko, John J ^b   Yagishita, Yoko ^b   Singh, Shivendra V ^b   Kensler, Thomas W ^a,b  

^a UNIVERSITY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH   (United States)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

Hepatotoxicity; Nrf2; Pten; Stress response; Withaferin A

Indexed keywords

KELCH LIKE ECH ASSOCIATED PROTEIN 1; PARACETAMOL; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; SULFORAPHANE; TRANSCRIPTION FACTOR NRF2; WITHAFERIN A; WITHANIA SOMNIFERA EXTRACT; CYTOTOXIN; KEAP1 PROTEIN, MOUSE; NFE2L2 PROTEIN, MOUSE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTECTIVE AGENT; PROTEIN KINASE B; PTEN PROTEIN, MOUSE; WITHANOLIDE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BINDING SITE; CELL PROTECTION; CONTROLLED STUDY; DRUG EFFICACY; DRUG POTENCY; DRUG TARGETING; GENE EXPRESSION; IN VITRO STUDY; IN VIVO STUDY; LIVER PROTECTION; LIVER TOXICITY; MALE; MOUSE; NONHUMAN; PLANT ROOT; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN INDUCTION; PROTEIN LOCALIZATION; SIGNAL TRANSDUCTION; TANDEM REPEAT; UPREGULATION; WITHANIA SOMNIFERA; ANIMAL; ANTAGONISTS AND INHIBITORS; C57BL MOUSE; CHEMISTRY; CYTOLOGY; DEFICIENCY; DRUG EFFECTS; FIBROBLAST; GENE EXPRESSION REGULATION; GENETICS; ISOLATION AND PURIFICATION; KNOCKOUT MOUSE; METABOLISM; PATHOLOGY; PRIMARY CELL CULTURE; TOXIC HEPATITIS; WITHANIA;

ACETAMINOPHEN; ANIMALS; CHEMICAL AND DRUG INDUCED LIVER INJURY; CYTOTOXINS; FIBROBLASTS; GENE EXPRESSION REGULATION; KELCH-LIKE ECH-ASSOCIATED PROTEIN 1; MALE; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; NF-E2-RELATED FACTOR 2; PHOSPHATIDYLINOSITOL 3-KINASES; PLANT ROOTS; PRIMARY CELL CULTURE; PROTECTIVE AGENTS; PROTO-ONCOGENE PROTEINS C-AKT; PTEN PHOSPHOHYDROLASE; SIGNAL TRANSDUCTION; WITHANIA; WITHANOLIDES;

EID: 84991728643     PISSN: 08915849     EISSN: 18734596     Source Type: Journal    
DOI: 10.1016/j.freeradbiomed.2016.10.003     Document Type: Article

References (80)

1. Palliyaguru, D.L., Singh, S.V., Kensler, T.W., Withania somnifera: from prevention to treatment of cancer. Mol. Nutr. Food Res. 60:6 (2016), 1342–1353.
2. Mirjalili, M.H., Moyano, E., Bonfill, M., Cusido, R.M., Palazon, J., Steroidal lactones from Withania somnifera, an ancient plant for novel medicine. Molecules 14 (2009), 2373–2393.
3. Hahm, E.R., Lee, J., Kim, S.H., Sehrawat, A., Arlotti, J.A., Shiva, S.S., et al. Metabolic alterations in mammary cancer prevention by withaferin A in a clinically relevant mouse model. J. Natl. Cancer Inst. 105 (2013), 1111–1122.
4. Manoharan, S., Panjamurthy, K., Menon, V.P., Balakrishnan, S., Alias, L.M., Protective effect of Withaferin-A on tumour formation in 7,12-dimethylbenz[a]anthracene induced oral carcinogenesis in hamsters. Indian J. Exp. Biol. 47 (2009), 16–23.
5. Li, W., Zhang, C., Du, H., Huang, V., Sun, B., Harris, J.P., et al. Withaferin A suppresses the up-regulation of acetyl-coA carboxylase 1 and skin tumor formation in a skin carcinogenesis mouse model. Mol. Carcinog., 2015, 10.1002/mc.22423.
6. Stan, S.D., Hahm, E.R., Warin, R., Singh, S.V., Withaferin A causes FOXO3a- and Bim-dependent apoptosis and inhibits growth of human breast cancer cells in vivo. Cancer Res. 68 (2008), 7661–7669.
7. Munagala, R., Kausar, H., Munjal, C., Gupta, R.C., Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells. Carcinogenesis 32 (2011), 1697–1705.
8. Nagalingam, A., Kuppusamy, P., Singh, S.V., Sharma, D., Saxena, N.K., Mechanistic elucidation of the antitumor properties of withaferin a in breast cancer. Cancer Res. 74 (2014), 2617–2629.
9. Reisman, S.A., Buckley, D.B., Tanaka, Y., Klaassen, C.D., CDDO-Im protects from acetaminophen hepatotoxicity through induction of Nrf2-dependent genes. Toxicol. Appl. Pharmacol. 236 (2009), 109–114.
10. Okawa, H., Motohashi, H., Kobayashi, A., Aburatani, H., Kensler, T.W., Yamamoto, M., Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem. Biophys. Res. Commun. 339 (2006), 79–88.
11. Fahey, J.W., Haristoy, X., Dolan, P.M., Kensler, T.W., Scholtus, I., Stephenson, K.K., et al. Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc. Natl. Acad. Sci. USA 99 (2002), 7610–7615.
12. Uruno, A., Furusawa, Y., Yagishita, Y., Fukutomi, T., Muramatsu, H., Negishi, T., et al. The Keap1-Nrf2 system prevents onset of diabetes mellitus. Mol. Cell. Biol. 33 (2013), 2996–3010.
13. Keleku-Lukwete, N., Suzuki, M., Otsuki, A., Tsuchida, K., Katayama, S., Hayashi, M., et al. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation. Proc. Natl. Acad. Sci. USA 112 (2015), 12169–12174.
14. Chen, P.C., Vargas, M.R., Pani, A.K., Smeyne, R.J., Johnson, D.A., Kan, Y.W., et al. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: critical role for the astrocyte. Proc. Natl. Acad. Sci. USA 106 (2009), 2933–2938.
15. 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 32 (2013), 3765–3781.
16. Rada, P., Rojo, A.I., Chowdhry, S., McMahon, M., Hayes, J.D., Cuadrado, A., SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol. Cell. Biol. 31 (2011), 1121–1133.
17. Wu, T., Zhao, F., Gao, B., Tan, C., Yagishita, N., Nakajima, T., et al. Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. Genes Dev. 28 (2014), 708–722.
18. Wakabayashi, N., Shin, S., Slocum, S.L., Agoston, E.S., Wakabayashi, J., Kwak, M.K., et al. Regulation of notch1 signaling by nrf2: implications for tissue regeneration. Sci. Signal., 3, 2010 ra52.
19. Wakabayashi, N., Skoko, J.J., Chartoumpekis, D.V., Kimura, S., Slocum, S.L., Noda, K., et al. Notch-Nrf2 axis: regulation of Nrf2 gene expression and cytoprotection by notch signaling. Mol. Cell. Biol. 34 (2014), 653–663.
20. Taguchi, K., Hirano, I., Itoh, T., Tanaka, M., Miyajima, A., Suzuki, A., et al. Nrf2 enhances cholangiocyte expansion in Pten-deficient livers. Mol. Cell. Biol. 34 (2014), 900–913.
21. Rojo, A.I., Rada, P., Mendiola, M., Ortega-Molina, A., Wojdyla, K., Rogowska-Wrzesinska, A., et al. The PTEN/NRF2 axis promotes human carcinogenesis. Antioxid. Redox Signal. 21 (2014), 2498–2514.
22. Rojo, A.I., Medina-Campos, O.N., Rada, P., Zuniga-Toala, A., Lopez-Gazcon, A., Espada, S., et al. Signaling pathways activated by the phytochemical nordihydroguaiaretic acid contribute to a Keap1-independent regulation of Nrf2 stability: role of glycogen synthase kinase-3. Free Radic. Biol. Med. 52 (2012), 473–487.
23. Lau, A., Zheng, Y., Tao, S., Wang, H., Whitman, S.A., White, E., et al. Arsenic inhibits autophagic flux, activating the Nrf2-Keap1 pathway in a p62-dependent manner. Mol. Cell. Biol. 33 (2013), 2436–2446.
24. Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236 (1997), 313–322.
25. Kong, X., Thimmulappa, R., Craciun, F., Harvey, C., Singh, A., Kombairaju, P., et al. Enhancing Nrf2 pathway by disruption of Keap1 in myeloid leukocytes protects against sepsis. Am. J. Respir. Crit. Care Med. 184 (2011), 928–938.
26. Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., O'Connor, T., Yamamoto, M., Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells 8 (2003), 379–391.
27. Yagishita, Y., Fukutomi, T., Sugawara, A., Kawamura, H., Takahashi, T., Pi, J., et al. Nrf2 protects pancreatic beta-cells from oxidative and nitrosative stress in diabetic model mice. Diabetes 63 (2014), 605–618.
28. McClain, C.J., Price, S., Barve, S., Devalarja, R., Shedlofsky, S., Acetamihen hepatotoxicity: an update. Curr. Gastroenterol. Rep. 1 (1999), 42–49.
29. Wakabayashi, N., Dinkova-Kostova, A.T., Holtzclaw, W.D., Kang, M.I., Kobayashi, A., Yamamoto, M., et al. 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. USA 101 (2004), 2040–2045.
30. Yang, Z., Garcia, A., Xu, S., Powell, D.R., Vertino, P.M., Singh, S., et al. Withania somnifera root extract inhibits mammary cancer metastasis and epithelial to mesenchymal transition. PLoS One, 8, 2013, e75069.
31. Cao, J., Schulte, J., Knight, A., Leslie, N.R., Zagozdzon, A., Bronson, R., et al. Prdx1 inhibits tumorigenesis via regulating PTEN/AKT activity. EMBO J. 28 (2009), 1505–1517.
32. Nguyen, H.N., Yang, J.M., Afkari, Y., Park, B.H., Sesaki, H., Devreotes, P.N., et al. Engineering ePTEN, an enhanced PTEN with increased tumor suppressor activities. Proc. Natl. Acad. Sci. USA 111 (2014), E2684–E2693.
33. Pfaffl, M.W., A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res., 29, 2001, e45.
34. Thimmulappa, R.K., Fuchs, R.J., Malhotra, D., Scollick, C., Traore, K., Bream, J.H., et al. Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid. Redox Signal. 9 (2007), 1963–1970.
35. Kensler, T.W., Wakabayashi, N., Nrf2: friend or foe for chemoprevention?. Carcinogenesis 31 (2010), 90–99.
36. Yates, M.S., Tran, Q.T., Dolan, P.M., Osburn, W.O., Shin, S., McCulloch, C.C., et al. Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis 30 (2009), 1024–1031.
37. Malhotra, D., Portales-Casamar, E., Singh, A., Srivastava, S., Arenillas, D., Happel, C., 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. 38 (2010), 5718–5734.
38. Takaya, K., Suzuki, T., Motohashi, H., Onodera, K., Satomi, S., Kensler, T.W., et al. Validation of the multiple sensor mechanism of the Keap1-Nrf2 system. Free Radic. Biol. Med. 53 (2012), 817–827.
39. Zhang, D.D., 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. 23 (2003), 8137–8151.
40. Hayes, J.D., Chowdhry, S., Dinkova-Kostova, A.T., Sutherland, C., Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of beta-TrCP and GSK-3. Biochem. Soc. Trans. 43 (2015), 611–620.
41. Li, M.H., Cha, Y.N., Surh, Y.J., Peroxynitrite induces HO-1 expression via PI3K/Akt-dependent activation of NF-E2-related factor 2 in PC12 cells. Free Radic. Biol. Med. 41 (2006), 1079–1091.
42. Martin, D., Rojo, A.I., Salinas, M., Diaz, R., Gallardo, G., Alam, J., et al. Regulation of heme oxygenase-1 expression through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol. J. Biol. Chem. 279 (2004), 8919–8929.
43. Prabu, P.C., Panchapakesan, S., Prenatal developmental toxicity evaluation of Withania somnifera root extract in Wistar rats. Drug Chem. Toxicol. 38 (2015), 50–56.
44. Antony, M.L., Lee, J., Hahm, E.R., Kim, S.H., Marcus, A.I., Kumari, V., et al. Growth arrest by the antitumor steroidal lactone withaferin A in human breast cancer cells is associated with down-regulation and covalent binding at cysteine 303 of beta-tubulin. J. Biol. Chem. 289 (2014), 1852–1865.
45. Bargagna-Mohan, P., Hamza, A., Kim, Y.E., Khuan Abby, H.Y., Mor-Vaknin, N., Wendschlag, N., et al. The tumor inhibitor and antiangiogenic agent withaferin A targets the intermediate filament protein vimentin. Chem. Biol. 14 (2007), 623–634.
46. Heyninck, K., Lahtela-Kakkonen, M., Van d, V., Haegeman, G., Vanden Berghe, W., Withaferin A inhibits NF-kappaB activation by targeting cysteine 179 in IKKbeta. Biochem. Pharmacol. 91 (2014), 501–509.
47. Santagata, S., Xu, Y.M., Wijeratne, E.M., Kontnik, R., Rooney, C., Perley, C.C., et al. Using the heat-shock response to discover anticancer compounds that target protein homeostasis. ACS Chem. Biol. 7 (2012), 340–349.
48. Hahm, E.R., Singh, S.V., Autophagy fails to alter withaferin A-mediated lethality in human breast cancer cells. Curr. Cancer Drug Targets 13 (2013), 640–650.
49. Rah, B., Ur, R.R., Nayak, D., Yousuf, S.K., Mukherjee, D., Kumar, L.D., et al. PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells. Autophagy 11 (2015), 314–331.
50. Lee, W., Kim, T.H., Ku, S.K., Min, K.J., Lee, H.S., Kwon, T.K., et al. Barrier protective effects of withaferin A in HMGB1-induced inflammatory responses in both cellular and animal models. Toxicol. Appl. Pharmacol. 262 (2012), 91–98.
51. Kaileh, M., Vanden Berghe, W., Heyerick, A., Horion, J., Piette, J., Libert, C., et al. Withaferin a strongly elicits IkappaB kinase beta hyperphosphorylation concomitant with potent inhibition of its kinase activity. J. Biol. Chem. 282 (2007), 4253–4264.
52. Yu, Y., Hamza, A., Zhang, T., Gu, M., Zou, P., Newman, B., et al. Withaferin A targets heat shock protein 90 in pancreatic cancer cells. Biochem. Pharmacol. 79 (2010), 542–551.
53. Wijeratne, E.M., Xu, Y.M., Scherz-Shouval, R., Marron, M.T., Rocha, D.D., Liu, M.X., et al. Structure-activity relationships for withanolides as inducers of the cellular heat-shock response. J. Med. Chem. 57 (2014), 2851–2863.
54. Thaiparambil, J.T., Bender, L., Ganesh, T., Kline, E., Patel, P., Liu, Y., et al. Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation. Int. J. Cancer 129 (2011), 2744–2755.
55. Sudhir, S., Budhiraja, R.D., Comparison of the protective effect of Withaferin-‘A’ and hydrocortisone against CCL4 induced hepatotoxicity in rats. Indian J. Physiol. Pharmacol. 36 (1992), 127–129.
56. Jadeja, R.N., Urrunaga, N.H., Dash, S., Khurana, S., Saxena, N.K., Withaferin-A reduces acetaminophen-induced liver injury in mice. Biochem. Pharmacol. 97 (2015), 122–132.
57. Lee, J., Liu, J., Feng, X., Salazar Hernandez, M.A., Mucka, P., Ibi, D., et al. Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice. Nat. Med. 22 (2016), 1023–1032.
58. Challa, A.A., Vukmirovic, M., Blackmon, J., Stefanovic, B., Withaferin-A reduces type I collagen expression in vitro and inhibits development of myocardial fibrosis in vivo. PLoS One, 7, 2012, e42989.
59. Kansanen, E., Bonacci, G., Schopfer, F.J., Kuosmanen, S.M., Tong, K.I., Leinonen, H., et al. Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 cysteine 151-independent mechanism. J. Biol. Chem. 286 (2011), 14019–14027.
60. Saito, R., Suzuki, T., Hiramoto, K., Asami, S., Naganuma, E., Suda, H., et al. Characterizations of three major cysteine sensors of Keap1 in stress response. Mol. Cell. Biol. 36:2 (2015), 271–284.
61. Na, H.K., Kim, E.H., Jung, J.H., Lee, H.H., Hyun, J.W., Surh, Y.J., (-)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells. Arch. Biochem. Biophys. 476 (2008), 171–177.
62. Jakubikova, J., Sedlak, J., Mithen, R., Bao, Y., Role of PI3K/Akt and MEK/ERK signaling pathways in sulforaphane- and erucin-induced phase II enzymes and MRP2 transcription, G2/M arrest and cell death in Caco-2 cells. Biochem. Pharmacol. 69 (2005), 1543–1552.
63. Abbaoui, B., Riedl, K.M., Ralston, R.A., Thomas-Ahner, J.M., Schwartz, S.J., Clinton, S.K., et al. Inhibition of bladder cancer by broccoli isothiocyanates sulforaphane and erucin: characterization, metabolism, and interconversion. Mol. Nutr. Food Res. 56 (2012), 1675–1687.
64. Keum, Y.S., Yu, S., Chang, P.P., Yuan, X., Kim, J.H., Xu, C., et al. Mechanism of action of sulforaphane: inhibition of p38 mitogen-activated protein kinase isoforms contributing to the induction of antioxidant response element-mediated heme oxygenase-1 in human hepatoma HepG2 cells. Cancer Res. 66 (2006), 8804–8813.
65. Manandhar, S., Cho, J.M., Kim, J.A., Kensler, T.W., Kwak, M.K., Induction of Nrf2-regulated genes by 3H-1, 2-dithiole-3-thione through the ERK signaling pathway in murine keratinocytes. Eur. J. Pharmacol. 577 (2007), 17–27.
66. Pitha-Rowe, I., Liby, K., Royce, D., Sporn, M., Synthetic triterpenoids attenuate cytotoxic retinal injury: cross-talk between Nrf2 and PI3K/AKT signaling through inhibition of the lipid phosphatase PTEN. Investig. Ophthalmol. Vis. Sci. 50 (2009), 5339–5347.
67. Heyninck, K., Sabbe, L., Chirumamilla, C.S., Szarc Vel, S.K., Vander, V.P., Lemmens, K.J., et al. Withaferin A induces heme oxygenase (HO-1) expression in endothelial cells via activation of the Keap1/Nrf2 pathway. Biochem. Pharmacol. 109 (2016), 48–61.
68. Hopkins, B.D., Hodakoski, C., Barrows, D., Mense, S.M., Parsons, R.E., PTEN function: the long and the short of it. Trends Biochem. Sci. 39 (2014), 183–190.
69. Spinelli, L., Lindsay, Y.E., Leslie, N.R., PTEN inhibitors: an evaluation of current compounds. Adv. Biol. Regul. 57 (2015), 102–111.
70. Leslie, N.R., Bennett, D., Lindsay, Y.E., Stewart, H., Gray, A., Downes, C.P., Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J. 22 (2003), 5501–5510.
71. Lee, S.R., Yang, K.S., Kwon, J., Lee, C., Jeong, W., Rhee, S.G., Reversible inactivation of the tumor suppressor PTEN by H2O2. J. Biol. Chem. 277 (2002), 20336–20342.
72. Connor, K.M., Subbaram, S., Regan, K.J., Nelson, K.K., Mazurkiewicz, J.E., Bartholomew, P.J., et al. Mitochondrial H2O2 regulates the angiogenic phenotype via PTEN oxidation. J. Biol. Chem. 280 (2005), 16916–16924.
73. Wu, K.L., Wu, C.A., Wu, C.W., Chan, S.H., Chang, A.Y., Chan, J.Y., Redox-sensitive oxidation and phosphorylation of PTEN contribute to enhanced activation of PI3K/Akt signaling in rostral ventrolateral medulla and neurogenic hypertension in spontaneously hypertensive rats. Antioxid. Redox Signal. 18 (2013), 36–50.
74. Jin, Q., Jhun, B.S., Lee, S.H., Lee, J., Pi, Y., Cho, Y.H., et al. Differential regulation of phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase, and AMP-activated protein kinase pathways during menadione-induced oxidative stress in the kidney of young and old rats. Biochem. Biophys. Res. Commun. 315 (2004), 555–561.
75. Satoh, H., Moriguchi, T., Saigusa, D., Baird, L., Yu, L., Rokutan, H., et al. NRF2 intensifies host defense systems to prevent lung carcinogenesis, but after tumor initiation accelerates malignant cell growth. Cancer Res. 76:10 (2016), 3088–3096.
76. Rolfs, F., Huber, M., Kuehne, A., Kramer, S., Haertel, E., Muzumdar, S., et al. Nrf2 activation promotes keratinocyte survival during early skin carcinogenesis via metabolic alterations. Cancer Res. 75 (2015), 4817–4829.
77. Wang, H., Liu, X., Long, M., Huang, Y., Zhang, L., Zhang, R., et al. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis. Sci. Transl. Med., 8, 2016 (334ra51).
78. Li, Y., Su, J., DingZhang, X., Zhang, J., Yoshimoto, M., Liu, S., et al. PTEN deletion and heme oxygenase-1 overexpression cooperate in prostate cancer progression and are associated with adverse clinical outcome. J. Pathol. 224 (2011), 90–100.
79. Lavrovsky, Y., Schwartzman, M.L., Abraham, N.G., Novel regulatory sites of the human heme oxygenase-1 promoter region. Biochem. Biophys. Res. Commun. 196 (1993), 336–341.
80. 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 20 (2009), 1606–1617.