title: Oxaliplatin activates the Keap1/Nrf2 antioxidant system conferring protection against the cytotoxicity of anticancer drugs.
abstract: Oxaliplatin is an important drug in the treatment of advanced metastatic colorectal cancer. NF-E2 p45-related factor 2 (Nrf2) is a key transcription factor that controls genes encoding cytoprotective and detoxifying enzymes through antioxidant-response elements (AREs) in their regulatory regions. Here, we report that oxaliplatin is an activator of the Nrf2 signaling pathway, with upregulation of ARE-driven genes and glutathione elevation. An injection of oxaliplatin into mice enhanced the expression of glutathione transferases and antioxidant enzymes in the small and large intestines of wild-type (WT) mice but not Nrf2(-/-) mice, indicating that oxaliplatin activates Nrf2 in vivo. Oxaliplatin failed to increase Nrf2 accumulation in non-small-cell lung cancer A549 cells, which harbor a dysfunctional somatic mutation of KEAP1. However, forced expression of WT mKeap1 restored the ability of oxaliplatin to activate the transcription factor. Cys(151) in Keap1 was required for the response stimulated by oxaliplatin. In addition, dichloro(1,2-diaminocyclohexane) platinum, a metabolite of oxaliplatin, was found to have the same effect in activating the ARE-gene battery as its parent drug, whereas another metabolite, oxalate, was ineffective. Moreover, two other platinum derivatives, cisplatin and carboplatin, had no effect on the Keap1/Nrf2 system. Furthermore, activation of Nrf2 by oxaliplatin reduced the sensitivity of colon cancer cells to therapeutic drugs. Conversely, knockdown of Nrf2 by Nrf2 siRNA reduced oxaliplatin-induced chemoresistance. Our study showed that oxaliplatin exerts protection against the cytotoxicity of anticancer drugs via Nrf2, indicating an important role of Nrf2 in oxaliplatin-based chemotherapy.
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China. Electronic address: xjwang@zju.edu.cn.
authors.forename: Xiu Jun
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China.
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China; Department of Biochemistry and Genetics,School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Genetics,School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China.
authors.forename: Zhexu
authors.initials: Z
authors.lastname: Chi
authors.affiliation: Department of Biochemistry and Genetics,School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China.
authors.forename: Ai
authors.initials: A
authors.lastname: Xin
authors.affiliation: Department of Biochemistry and Genetics,School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China.
authors.forename: Jiaguo
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Genetics,School of Medicine, Zhejiang University, Hangzhou 310058, People׳s Republic of China. Electronic address: xiuwentang@zju.edu.cn.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Tang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D061745:Antioxidant Response Elements / Q000235:genetics; D000975:Antioxidants / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D000975:Antioxidants; D003598:Cytoskeletal Proteins; D005609:Free Radicals; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin
keywords: Antioxidant enzymes; Chemoresistance; Colon cancer cells; Free radicals; Nrf2; Oxaliplatin