转录因子Nrf2在癌症化学预防与化疗耐药性中的调控和功能

doi:10.5246/jcps.2011.01.001

摘要/Abstract

摘要：

化学疗法和化学预防是控制癌症发病率和死亡率的重要手段, 而针对氧化性/亲电性胁迫的细胞防御机制对这两种手段中都有重要影响。这种细胞防御机制主要由代谢消除氧化性/亲电性物种的细胞保护酶和蛋白组成, 而转录因子Nrf2调控着很多这些酶和蛋白的基础和可诱导表达, 是协调细胞防御响应的枢纽。Keap1蛋白可以感受氧化性/亲电性信号, 正常情况下与Nrf2结合并抑制其活性。在氧化性/亲电性胁迫下, 这种结合被破坏并导致Nrf2的激活和细胞保护酶/蛋白的表达。因此, Nrf2成为了化学预防药物的重要作用靶标。然而, 在不同细胞环境下Nrf2的激活可能导致完全不同的后果。Nrf2对细胞不加区别的保护作用在癌症发生和癌细胞化疗耐药性中扮演了不受欢迎的角色。Nrf2信号的激活给癌变细胞以生长优势, 也保护癌细胞免受化疗药物杀伤, 导致不良的临床后果。从这方面而言, Nrf2信号的抑制剂可以增强化疗药物的效果, 也值得深入研究开发。而对Nrf2的调控和功能的深入研究和了解, 对化学预防和化学治疗都具有重要意义。

关键词: Nrf2, 氧化性/亲电性胁迫, 癌症发生, 化学预防, 化疗耐药性

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

中图分类号:

R915

Supporting:

Foundation item: Ministry of Science and Technology of China (The National Basic research Program of China, Grant No. 2009CB526509).

^*Corresponding author. Tel: 86-10-82801539

阙琳玲, 王荟霞, 曹宝山, 杨晓达, 王夔, 余四旺^*. 转录因子Nrf2在癌症化学预防与化疗耐药性中的调控和功能[J]. , DOI: 10.5246/jcps.2011.01.001.

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.

参考文献

[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.