title: Rexinoid inhibits Nrf2-mediated transcription through retinoid X receptor alpha.
abstract: 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. We reported recently that retinoid X receptor alpha (RXRα) inhibits Nrf2 function by direct interaction with the Neh7 domain of Nrf2 in a ligand-independent manner. Here, we provide evidence that an RXRα-specific ligand, bexarotene, dose-dependently inhibits the mRNA expression of ARE-driven genes. Knock-down of RXRα by siRNA abolished the inhibitory effect of bexarotene. Conversely, the over-expression of RXRα enhanced the inhibition by bexarotene, indicating that the effect is mediated by RXRα. The inhibition by bexarotene was also found in the non-small-cell lung cancer cell line A549, which carries a dysfunctional somatic mutation of Kelch-like ECH-associated protein 1 (KEAP1), suggesting that KEAP1 is not involved. Our results demonstrate that rexinoid is able to inhibit the transcriptional activity of Nrf2, and that RXRα can repress the cytoprotection pathway in a ligand-dependent manner.
authors.affiliation: Division of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: Jiaguo
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, PR China. Electronic address: xiuwentang@zju.edu.cn.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Tang
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D061745:Antioxidant Response Elements; D000077610:Bexarotene; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: D016588:Anticarcinogenic Agents; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D047490:Retinoid X Receptor alpha; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene
keywords: Bexarotene; Nrf2; RXRα