6 [17] K. Taguchi, H. Motohashi, and M. Yamamoto, “Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution,” Genes to Cells, vol. 16, no. 2, pp. 123–140, 2011. [18] E. Kansanen, H.-K. Jyrkka¨nen, and A.-L. Levonen, “Activation of stress signaling pathways by electrophilic oxidized and nitrated lipids,” Free Radical Biology and Medicine, vol. 52, no. 6, pp. 973–982, 2012. [19] K. A. Jung and M. K. Kwak, “The Nrf2 system as a potential target for the development of indirect antioxidants,” Molecules, vol. 15, no. 10, pp. 7266–7291, 2010. [20] M. Ramos-Gomez, M. K. Kwak, P. M. Dolan et al., “Sensitivity to carcinogenesis is increased and chemoprotective eﬃcacy of enzyme inducers is lost in nrf2 transcription factor-deﬁcient mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 6, pp. 3410–3415, 2001. [21] T. O. Khor, M. T. Huang, K. H. Kwon, J. Y. Chan, B. S. Reddy, and A. N. Kong, “Nrf2-deﬁcient mice have an increased susceptibility to dextran sulfate sodium-induced colitis,” Cancer Research, vol. 66, no. 24, pp. 11580–11584, 2006. [22] T. O. Khor, M. T. Huang, A. Prawan et al., “Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer,” Cancer Prevention Research, vol. 1, no. 3, pp. 187–191, 2008. [23] W. O. Osburn, B. Karim, P. M. Dolan et al., “Increased colonic inﬂammatory injury and formation of aberrant crypt foci in Nrf2-deﬁcient mice upon dextran sulfate treatment,” International Journal of Cancer, vol. 121, no. 9, pp. 1883–1891, 2007. [24] K. Chan, R. Lu, J. C. Chang, and Y. W. Kan, “NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development,” Proceed- ings of the National Academy of Sciences of the United States of America, vol. 93, no. 24, pp. 13943–13948, 1996. [25] N. Chen, X. Yi, N. Abushahin et al., “Nrf2 expression in endometrial serous carcinomas and its precancers,” Interna- tional Journal of Clinical and Experimental Pathology, vol. 4, no. 1, pp. 85–96, 2011. [26] X. Ma, J. Zhang, S. Liu, Y. Huang, B. Chen, and D. Wang, “Nrf2 knockdown by shRNA inhibits tumor growth and increases eﬃcacy of chemotherapy in cervical cancer,” Cancer Chemotherapy and Pharmacology, vol. 69, no. 2, pp. 485–494, 2012. [27] A. K. Bauer, H.-Y. Cho, L. Miller-DeGraﬀ et al., “Targeted deletion of Nrf2 reduces urethane-induced lung tumor devel- opment in mice,” PLoS One, vol. 6, no. 10, Article ID e26590, 2011. [28] J. D. Hayes and M. McMahon, “NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer,” Trends in Biochemical Sciences, vol. 34, no. 4, pp. 176–188, 2009. [29] B. Padmanabhan, K. I. Tong, T. Ohta et al., “Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer,” Molecular Cell, vol. 21, no. 5, pp. 689–700, 2006. [30] A. Singh, V. Misra, R. K. Thimmulappa et al., “Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer,” PLoS Medicine, vol. 3, no. 10, Article ID e420, 2006. [31] A. Singh, S. Boldin-Adamsky, R. K. Thimmulappa et al., “RNAi-mediated silencing of nuclear factor erythroid-2- related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases eﬃcacy of chemother- apy,” Cancer Research, vol. 68, no. 19, pp. 7975–7984, 2008. International Journal of Cell Biology [32] T. Shibata, A. Kokubu, M. Gotoh et al., “Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer,” Gastroenterology, vol. 135, no. 4, pp. 1358–1368, 2008. [33] P. Zhang, A. Singh, S. Yegnasubramanian et al., “Loss of kelch- like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth,” Molecular Cancer Therapeutics, vol. 9, no. 2, pp. 336–346, 2010. [34] T. Shibata, T. Ohta, K. I. Tong et al., “Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 36, pp. 13568–13573, 2008. [35] Y. R. Kim, J. E. Oh, M. S. Kim et al., “Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin,” Journal of Pathology, vol. 220, no. 4, pp. 446–451, 2010. [36] G. M. Denicola, F. A. Karreth, T. J. Humpton et al., “Oncogene-induced Nrf2 transcription promotes ROS detox- iﬁcation and tumorigenesis,” Nature, vol. 475, no. 7354, pp. 106–109, 2011. [37] M. K. Kwak, B. Huang, H. Chang, J. A. Kim, and T. W. Kensler, “Tissue speciﬁc increase of the catalytic subunits of the 26S proteasome by indirect antioxidant dithiolethione in mice: enhanced activity for degradation of abnormal protein,” Life Sciences, vol. 80, no. 26, pp. 2411–2420, 2007. [38] A. M. Pickering, A. L. Koop, C. Y. Teoh, G. Ermak, T. Grune, and K. J. A. Davies, “The immunoproteasome, the 20S proteasome and the PA28αβ proteasome regulator are oxidative-stress-adaptive proteolytic complexes,” Biochemical Journal, vol. 432, no. 3, pp. 585–594, 2010. [39] A. Arlt, I. Bauer, C. Schafmayer 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, vol. 28, no. 45, pp. 3983– 3996, 2009. [40] J. D. Hayes, J. U. Flanagan, and I. R. Jowsey, “Glutathione transferases,” Annual Review of Pharmacology and Toxicology, vol. 45, pp. 51–88, 2005. [41] H. Ikeda, S. Nishi, and M. Sakai, “Transcription factor Nrf2/MafK regulates rat placental glutathione S-transferase gene during hepatocarcinogenesis,” Biochemical Journal, vol. 380, no. 2, pp. 515–521, 2004. [42] V. Vollrath, A. M. Wielandt, M. Iruretagoyena, and J. Chianale, “Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene,” Biochemical Journal, vol. 395, no. 3, pp. 599–609, 2006. [43] J. M. Maher, X. Cheng, A. L. Slitt, M. Z. Dieter, and C. D. Klaassen, “Induction of the multidrug resistance-associated protein family of transporters by chemical activators of receptor-mediated pathways in mouse liver,” Drug Metabolism and Disposition, vol. 33, no. 7, pp. 956–962, 2005. [44] S. K. Kim, J. W. Yang, M. R. Kim et al., “Increased expression of Nrf2/ARE-dependent anti-oxidant proteins in tamoxifen-resistant breast cancer cells,” Free Radical Biology and Medicine, vol. 45, no. 4, pp. 537–546, 2008. [45] J. M. Cho, S. Manandhar, H. R. Lee, H. M. Park, and M. K. Kwak, “Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: implication to cancer cell resistance,” Cancer Letters, vol. 260, no. 1-2, pp. 96–108, 2008. [46] X. J. Wang, Z. Sun, N. F. Villeneuve et al., “Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2,” Carcinogenesis, vol. 29, no. 6, pp. 1235–1243, 2008.