The regulation and functions of transcription factor Nrf2 in cancer chemoprevention and chemoresistance

doi:10.5246/jcps.2011.01.001

Abstract

Abstract:

Chemotherapy and chemoprevention have been two of the most important means to control cancer incidence and mortality, and the cellular defensive machinery against oxidative/electrophilic stresses plays significant roles in both means. This defensive system is composed of cytoprotective enzymes that metabolize and eliminate oxidative/electrophilic species. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) controls the basal and inducible expression of many cytoprotective genes, and plays a pivotal role in coordinating cellular defensive responses. Under basal conditions, the activity of Nrf2 is inhibited by binding to Kelch-like ECH-associated protein 1 (Keap1), which is capable of sensing oxidative/electrophilic signals. Upon oxidative/electrophilic stresses, the binding of Nrf2 to Keap1 is disrupted, leading to activation of Nrf2 and induction of cytoprotective enzymes. Thus, Nrf2 has emerged as an important target of chemopreventive drugs. However, activation of Nrf2 could lead to very different outcomes depending on the cellular context. The indiscriminative protective effects of Nrf2 lead to its undesired functions in carcinogenesis and chemoresistance of cancer cells. Activation of Nrf2 provides neoplastic cells with growth advantages and protects cancer cells from chemotherapeutic drugs, resulting in poor clinical outcomes. In this means, inhibitors of Nrf2 signaling can enhance the efficacy of chemotherapeutic drugs and deserve further development. A better understanding of the regulation and functions of Nrf2 would be helpful for researches in both chemoprevention and chemotherapy of cancer.

Key words: Nrf2, Oxidative/electrophilic stress, Carcinogenesis, Chemoprevention, Chemoresistance

CLC Number:

R915

Supporting:

Lin-Ling Que, Hui-Xia Wang, Bao-Shan Cao, Xiao-Da Yang, Kui Wang, Si-Wang Yu^*. The regulation and functions of transcription factor Nrf2 in cancer chemoprevention and chemoresistance [J]. , DOI: 10.5246/jcps.2011.01.001.

References

[1] Jemal, A.; Siegel, R.; Xu, J.; Ward, E. CA Cancer J. Clin. 2010, 60, 277-300.
[2] Zhao, P.; Chen, W.Q. Chinese Cancer Registry Annual Report 2009. Military Medical Science Press, 2010.
[3] Yu, S.; Kong, A.N. Curr. Cancer Drug Targets. 2007, 7, 416-424.
[4] Carbone, M.; Pass, H.I. Semin. Cancer Biol. 2004, 14, 399-405.
[5] Melczer, N.; Hamar, M. Oncology. 1964, 18, 195-209.
[6] Trachootham, D.; Lu, W.; Ogasawara, M.A.; Nilsa, R.D.; Huang, P. Antioxid. Redox Signal. 2008, 10, 1343-1374.
[7] Mates, J.M.; Segura, J.A.; Alonso, F.J.; Marquez, J. Arch. Toxicol. 2008, 82, 273-299.
[8] Federico, A.; Morgillo, F.; Tuccillo, C.; Ciardiello, F.; Loguercio, C. Int. J. Cancer 2007, 121, 2381-2386.
[9] Allen, N.E.; Key, T.J. Nat. Rev. Urol. 2009, 6, 187-188.
[10] Goralczyk, R. Nutr. Cancer. 2009, 61, 767-774.
[11] Ahsan, H.; Parveen, N.; Khan, N.U.; Hadi, S.M. Chem. Biol. Interact. 1999, 121, 161-175.
[12] Yoshino, M.; Haneda, M.; Naruse, M.; Htay, H.H.; Tsubouchi, R.; Qiao, S.L.; Li, W.H.; Murakami, K.; Yokochi, T. Toxicol. In Vitro. 2004, 18, 783-789.
[13] Tarumoto, T.; Nagai, T.; Ohmine, K.; Miyoshi, T.; Nakamura, M.; Kondo, T.; Mitsugi, K.; Nakano, S.; Muroi, K.; Komatsu, N.; Ozawa, K. Exp. Hematol. 2004, 32, 375-381.
[14] Dinkova-Kostova, A.T.; Talalay, P. Mol. Nutr. Food Res. 2008, 52, Suppl 1, S128-138.
[15] Hayes, J.D.; McMahon, M. Trends Biochem. Sci. 2009, 34, 176-188.
[16] Niture, S.K.; Kaspar, J.W.; Shen, J.; Jaiswal, A.K. Toxicol. Appl. Pharmacol. 2010, 244, 37-42.
[17] Hayes, J.D.; McMahon, M.; Chowdhry, S.; Dinkova-Kostova, A.T. Antioxid. Redox Signal. 2010, 13, 1713-1748.
[18] Itoh, K.; Wakabayashi, N.; Katoh, Y.; Ishii, T.; Igarashi, K.; Engel, J.D.; Yamamoto, M. Genes Dev. 1999, 13, 76-86.
[19] Itoh, K.; Ishii, T.; Wakabayashi, N.; Yamamoto, M. Free Radic. Res. 1999, 31, 319-324.
[20] Moi, P.; Chan, K.; Asunis, I.; Cao, A.; Kan, Y.W. Proc. Natl. Acad. Sci. USA. 1994, 91, 9926-9930.
[21] Itoh, K.; Igarashi, K.; Hayashi, N.; Nishizawa, M.; Yamamoto, M. Mol. Cell Biol. 1995, 15, 4184-4193.
[22] Venugopal, R.; Jaiswal, A.K. Proc. Natl. Acad. Sci. USA. 1996, 93, 14960-14965.
[23] Dinkova-Kostova, A.T.; Holtzclaw, W.D.; Cole, R.N.; Itoh, K.; Wakabayashi, N.; Katoh, Y.; Yamamoto, M.; Talalay, P. Proc. Natl. Acad. Sci. USA. 2002, 99, 11908-11913.
[24] Itoh, K.; Wakabayashi, N.; Katoh, Y.; Ishii, T.; O'Connor, T.; Yamamoto, M. Genes Cells. 2003, 8, 379-391.
[25] Itoh, K.; Mimura, J.; Yamamoto, M. Antioxid. Redox Signal. 2010, 13, 1665-1678.
[26] McMahon, M.; Itoh, K.; Yamamoto, M.; Hayes, J.D. J. Biol. Chem. 2003, 278, 21592-21600.
[27] Zhang, D.D.; Hannink, M. Mol. Cell Biol. 2003, 23, 8137-8151.
[28] Nioi, P.; Nguyen, T.; Sherratt, P.J.; Pickett, C.B. Mol. Cell Biol. 2005, 25, 10895-10906.
[29] Katoh, Y.; Itoh, K.; Yoshida, E.; Miyagishi, M.; Fukamizu, A.; Yamamoto, M. Genes Cells. 2001, 6, 857-868.
[30] McMahon, M.; Thomas, N.; Itoh, K.; Yamamoto, M.; Hayes, J.D. J. Biol. Chem. 2004, 279, 31556-31567.
[31] Dhakshinamoorthy, S.; Jaiswal, A.K. Oncogene. 2001, 20, 3906-3917.
[32] Holland, R.; Fishbein, J.C. Antioxid. Redox Signal. 2010, 13, 1749-1761.
[33] Kobayashi, A.; Kang, M.I.; Okawa, H.; Ohtsuji, M.; Zenke, Y.; Chiba, T.; Igarashi, K.; Yamamoto, M. Mol. Cell Biol. 2004, 24, 7130-7139.
[34] Cullinan, S.B.; Gordan, J.D.; Jin, J.; Harper, J.W.; Diehl, J.A. Mol. Cell Biol. 2004, 24, 8477-8486.
[35] Padmanabhan, B.; Tong, K.I.; Ohta, T.; Nakamura, Y.; Scharlock, M.; Ohtsuji, M.; Kang, M.I.; Kobayashi, A.; Yokoyama, S.; Yamamoto, M. Mol. Cell. 2006, 21, 689-700.
[36] Tong, K.I.; Padmanabhan, B.; Kobayashi, A.; Shang, C.; Hirotsu, Y.; Yokoyama, S.; Yamamoto, M. Mol. Cell Biol. 2007, 27, 7511-7521.
[37] Li, X.; Zhang, D.; Hannink, M.; Beamer, L.J. J. Biol. Chem. 2004, 279, 54750-54758.
[38] Tong, K.I.; Kobayashi, A.; Katsuoka, F.; Yamamoto, M. Biol. Chem. 2006, 387, 1311-1320.
[39] Itoh, K.; Chiba, T.; Takahashi, S.; Ishii, T.; Igarashi, K.; Katoh, Y.; Oyake, T.; Hayashi, N.; Satoh, K.; Hatayama, I.; Yamamoto, M.; Nabeshima, Y. Biochem. Biophys. Res. Commun. 1997, 236, 313-322.
[40] Jain, A.K.; Bloom, D.A.; Jaiswal, A.K. J. Biol. Chem. 2005, 280, 29158-29168.
[41] Li, W.; Yu, S.W.; Kong, A.N. J. Biol. Chem. 2006, 281, 27251-27263.
[42] Theodore, M.; Kawai, Y.; Yang, J.; Kleshchenko, Y.; Reddy, S.P.; Villalta, F.; Arinze, I.J. J. Biol. Chem. 2008, 283, 8984-8994.
[43] Li, W.; Jain, M.R.; Chen, C.; Yue, X.; Hebbar, V.; Zhou, R.; Kong, A.N. J. Biol. Chem. 2005, 280, 28430-28438.
[44] Huang, H.C.; Nguyen, T.; Pickett, C.B. J. Biol. Chem. 2002, 277, 42769-42774.
[45] Kong, A.N.; Owuor, E.; Yu, R.; Hebbar, V.; Chen, C.; Hu, R.; Mandlekar, S. Drug Metab. Rev. 2001, 33, 255-271.
[46] Cullinan, S.B.; Zhang, D.; Hannink, M.; Arvisais, E.; Kaufman, R.J.; Diehl, J.A. Mol. Cell Biol. 2003, 23, 7198-7209.
[47] Rojo, A.I.; Sagarra, M.R.; Cuadrado, A. J. Neurochem. 2008, 105, 192-202.
[48] Jain, A.K.; Jaiswal, A.K. J. Biol. Chem. 2007, 282, 16502-16510.
[49] Kaspar, J.W.; Jaiswal, A.K. FASEB J. 2010.
[50] Apopa, P.L.; He, X.; Ma, Q. J. Biochem. Mol. Toxicol. 2008, 22, 63-76.
[51] Sun, J.; Hoshino, H.; Takaku, K.; Nakajima, O.; Muto, A.; Suzuki, H.; Tashiro, S.; Takahashi, S.; Shibahara, S.; Alam, J.; Taketo, M.M.; Yamamoto, M.; Igarashi, K. EMBO J. 2002, 21, 5216-5224.
[52] Nguyen, T.; Huang, H.C.; Pickett, C.B. J. Biol. Chem. 2000, 275, 15466-15473.
[53] Brown, S.L.; Sekhar, K.R.; Rachakonda, G.; Sasi, S.; Freeman, M.L. Cancer Res. 2008, 68, 364-368.
[54] Ikeda, Y.; Sugawara, A.; Taniyama, Y.; Uruno, A.; Igarashi, K.; Arima, S.; Ito, S.; Takeuchi, K. J. Biol. Chem. 2000, 275, 33142-33150.
[55] Wang, X.J.; Hayes, J.D.; Henderson, C.J.; Wolf, C.R. Proc. Natl. Acad. Sci. USA. 2007, 104, 19589-19594.
[56] Kwak, M.K.; Itoh, K.; Yamamoto, M.; Kensler, T.W. Mol. Cell Biol. 2002, 22, 2883-2892.
[57] Lee, O.H.; Jain, A.K.; Papusha, V.; Jaiswal, A.K. J. Biol. Chem. 2007, 282, 36412-36420.
[58] Kwak, M.K.; Wakabayashi, N.; Greenlaw, J.L.; Yamamoto, M.; Kensler, T.W. Mol. Cell Biol. 2003, 23, 8786-8794.
[59] Cho, H.Y.; Jedlicka, A.E.; Reddy, S.P.; Kensler, T.W.; Yamamoto, M.; Zhang, L.Y.; Kleeberger, S.R. Am. J. Respir. Cell Mol. Biol. 2002, 26, 175-182.
[60] Chan, K.; Han, X.D.; Kan, Y.W. Proc. Natl. Acad. Sci. USA. 2001, 98, 4611-4616.
[61] Ramos-Gomez, M.; Kwak, M.K.; Dolan, P.M.; Itoh, K.; Yamamoto, M.; Talalay, P.; Kensler, T.W. Proc. Natl. Acad. Sci. USA. 2001, 98, 3410-3415.
[62] Okawa, H.; Motohashi, H.; Kobayashi, A.; Aburatani, H.; Kensler, T.W.; Yamamoto, M. Biochem. Biophys. Res. Commun. 2006, 339, 79-88.
[63] Zhang, D.D. Antioxid. Redox Signal. 2010, 13, 1623-1626.
[64] Holtzclaw, W.D.; Dinkova-Kostova, A.T.; Talalay, P. Adv. Enzyme Regul. 2004, 44, 335-367.
[65] van Iersel, M.L.; Verhagen, H.; van Bladeren, P.J. Mutat. Res. 1999, 443, 259-270.
[66] Wattenberg, L.W. J. Natl. Cancer Inst. 1972, 48, 1425-1430.
[67] Jana, S.; Mandlekar, S. Curr. Drug Metab. 2009, 10, 595-616.
[68] Sheweita, S.A.; Tilmisany, A.K. Curr. Drug Metab. 2003, 4, 45-58.
[69] Talalay, P.; De Long, M.J.; Prochaska, H.J. Proc. Natl. Acad. Sci. USA. 1988, 85, 8261-8265.
[70] Friling, R.S.; Bergelson, S.; Daniel, V. Proc. Natl. Acad. Sci. USA. 1992, 89, 668-672.
[71] Wang, X.; Tomso, D.J.; Chorley, B.N.; Cho, H.Y.; Cheung, V.G.; Kleeberger, S.R.; Bell, D.A. Hum. Mol. Genet. 2007, 16, 1188-1200.
[72] Chan, K.; Kan, Y.W. Proc. Natl. Acad. Sci. USA. 1999, 96, 12731-12736.
[73] Wakabayashi, N.; Itoh, K.; Wakabayashi, J.; Motohashi, H.; Noda, S.; Takahashi, S.; Imakado, S.; Kotsuji, T.; Otsuka, F.; Roop, D.R.; Harada, T.; Engel, J.D.; Yamamoto, M. Nat. Genet. 2003, 35, 238-245.
[74] Osburn, W.O.; Yates, M.S.; Dolan, P.D.; Chen, S.; Liby, K.T.; Sporn, M.B.; Taguchi, K.; Yamamoto, M.; Kensler, T.W. Toxicol. Sci. 2008, 104, 218-227.
[75] Aoki, Y.; Sato, H.; Nishimura, N.; Takahashi, S.; Itoh, K.; Yamamoto, M. Toxicol. Appl. Pharmacol. 2001, 173, 154-160.
[76] Khor, T.O.; Huang, M.T.; Prawan, A.; Liu, Y.; Hao, X.; Yu, S.; Cheung, W.K.; Chan, J.Y.; Reddy, B.S.; Yang, C.S.; Kong, A.N. Cancer Prev. Res (Phila). 2008, 1, 187-191.
[77] Xu, C.; Huang, M.T.; Shen, G.; Yuan, X.; Lin, W.; Khor, T.O.; Conney, A.H.; Kong, A.N. Cancer Res. 2006, 66, 8293-8296.
[78] Fahey, J.W.; Haristoy, X.; Dolan, P.M.; Kensler, T.W.; Scholtus, I.; Stephenson, K.K.; Talalay, P.; Lozniewski, A. Proc. Natl. Acad. Sci. USA. 2002, 99, 7610-7615.
[79] Hinman, A.; Chuang, H.H.; Bautista, D.M.; Julius, D. Proc. Natl. Acad. Sci. USA. 2006, 103, 19564-19568.
[80] Kensler, T.W.; Wakabayashi, N. Carcinogenesis. 2010, 31, 90-99.
[81] Lonning, P.E. Mol. Oncol. 2010, 4, 284-300.
[82] Meijerman, I.; Beijnen, J.H.; Schellens, J.H. Cancer Treat. Rev. 2008, 34, 505-520.
[83] Schor, N.F.; Kagan, V.E.; Liang, Y.; Yan, C.; Tyurina, Y.; Tyurin, V.; Nylander, K.D. Biochemistry (Mosc). 2004, 69, 38-44.
[84] Chen, H.H.; Kuo, M.T. Met. Based Drugs. 2010, 2010.
[85] Lau, A.; Villeneuve, N.F.; Sun, Z.; Wong, P.K.; Zhang, D.D. Pharmacol. Res. 2008, 58, 262-270.
[86] Hayashi, A.; Suzuki, H.; Itoh, K.; Yamamoto, M.; Sugiyama, Y. Biochem. Biophys. Res. Commun. 2003, 310, 824-829.
[87] Shen, G.; Kong, A.N. Biopharm. Drug Dispos. 2009, 30, 345-355.
[88] Maher, J.M.; Cheng, X.; Slitt, A.L.; Dieter, M.Z.; Klaassen, C.D. Drug Metab. Dispos. 2005, 33, 956-962.
[89] Maher, J.M.; Dieter, M.Z.; Aleksunes, L.M.; Slitt, A.L.; Guo, G.; Tanaka, Y.; Scheffer, G.L.; Chan, J.Y.; Manautou, J.E.; Chen, Y.; Dalton, T.P.; Yamamoto, M.; Klaassen, C.D. Hepatology. 2007, 46, 1597-1610.
[90] Cho, J.M.; Manandhar, S.; Lee, H.R.; Park, H.M.; Kwak, M.K. Cancer Lett. 2008, 260, 96-108.
[91] Singh, A.; Boldin-Adamsky, S.; Thimmulappa, R.K.; Rath, S.K.; Ashush, H.; Coulter, J.; Blackford, A.; Goodman, S.N.; Bunz, F.; Watson, W.H.; Gabrielson, E.; Feinstein, E.; Biswal, S. Cancer Res. 2008, 68, 7975-7984.
[92] Kim, H.R.; Kim, S.; Kim, E.J.; Park, J.H.; Yang, S.H.; Jeong, E.T.; Park, C.; Youn, M.J.; So. H.S.; Park, R. Lung Cancer. 2008, 60, 47-56.
[93] Akhdar, H.; Loyer, P.; Rauch, C.; Corlu, A.; Guillouzo, A.; Morel, F. Eur. J. Cancer. 2009, 45, 2219-2227.
[94] Manandhar, S.; Lee, S.; Kwak, M.K. Arch. Pharm. Res. 2010, 33, 717-726.
[95] Jiang, T.; Chen, N.; Zhao, F.; Wang, X.J.; Kong, B.; Zheng, W.; Zhang, D.D. Cancer Res. 2010, 70, 5486-5496.
[96] Hu, L.; Miao, W.; Loignon, M.; Kandouz, M.; Batist, G. Cancer Chemother. Pharmacol. 2010, 66, 467-474.
[97] Shibata, T.; Ohta, T.; Tong, K.I.; Kokubu, A.; Odogawa, R.; Tsuta, K.; Asamura, H.; Yamamoto, M.; Hirohashi, S. Proc. Natl. Acad. Sci. USA. 2008, 105, 13568-13573.
[98] Homma, S.; Ishii, Y.; Morishima, Y.; Yamadori, T.; Matsuno, Y.; Haraguchi, N.; Kikuchi, N.; Satoh, H.; Sakamoto, T.; Hizawa, N.; Itoh, K.; Yamamoto, M. Clin. Cancer Res. 2009, 15, 3423-3432.
[99] Solis, L.M.; Behrens, C.; Dong, W.; Suraokar, M.; Ozburn, N.C.; Moran, C.A.; Corvalan, A.H.; Biswal, S.; Swisher, S.G.; Bekele, B.N.; Minna, J.D.; Stewart, D.J.; Wistuba, II. Clin. Cancer Res. 2010, 16, 3743-3753.
[100] Wang, J.; Zhang, M.; Zhang, L.; Cai, H.; Zhou, S.; Zhang J.; Wang, Y. J. Surg. Res. 2010, 164, e99-105.
[101] Ikeda, H.; Nishi, S.; Sakai, M. Biochem J. 2004, 380, 515-521.
[102] Ohta, T.; Iijima, K.; Miyamoto, M.; Nakahara, I.; Tanaka, H.; Ohtsuji, M.; Suzuki, T.; Kobayashi, A.; Yokota, J.; Sakiyama, T.; Shibata, T.; Yamamoto, M.; Hirohashi, S. Cancer Res. 2008, 68, 1303-1309.
[103] Chen, J.; Shaikh, Z.A. Toxicol. Appl. Pharmacol. 2009, 241, 81-89.
[104] Pi, J.; Diwan, B.A.; Sun, Y.; Liu, J.; Qu, W.; He, Y.; Styblo, M.; Waalkes, M.P. Free Radic. Biol. Med. 2008, 45, 651-658.
[105] Shibata, T.; Kokubu, A.; Gotoh, M.; Ojima, H.; Ohta, T.; Yamamoto, M.; Hirohashi, S. Gastroenterology. 2008, 135, 1358-1368.
[106] Wang, R.; An, J.; Ji, F.; Jiao, H.; Sun, H.; Zhou, D. Biochem. Biophys. Res. Commun. 2008, 373, 151-154.
[107] Barve, A.; Khor, T.O.; Nair, S.; Reuhl, K.; Suh, N.; Reddy, B.; Newmark, H.; Kong, A.N. Int. J. Cancer. 2009, 124, 1693-1699.
[108] Frohlich, D.A.; McCabe, M.T.; Arnold, R.S.; Day, M.L. Oncogene. 2008, 27, 4353-4362.
[109] Yu, S.; Khor, T.O.; Cheung, K.L.; Li, W.; T. Wu, Y.; Huang, Y.; Foster, B.A.; Kan, Y.W.; Kong, A.N. PLoS One. 2010, 5, e8579.