title: Farnesoid X receptor antagonizes JNK signaling pathway in liver carcinogenesis by activating SOD3.
abstract: The farnesoid X receptor (FXR) is a key metabolic and homeostatic regulator in the liver. In the present work, we identify a novel role of FXR in antagonizing c-Jun N-terminal kinase (JNK) signaling pathway in liver carcinogenesis by activating superoxide dismutase 3 (SOD3) transcription. Compared with wild-type mouse liver, FXR(-/-) mouse liver showed elevated JNK phosphorylation. JNK1 deletion suppressed the increase of diethylnitrosamine-induced tumor number in FXR(-/-) mice. These results suggest that JNK1 plays a key role in chemical-induced liver carcinogenesis in FXR(-/-) mice. We found that ligand-activated FXR was able to alleviate H₂O₂or tetradecanoylphorbol acetate-induced JNK phosphorylation in human hepatoblastoma (HepG2) cells or mouse primary hepatocytes. FXR ligand decreased H₂O₂-induced reactive oxygen species (ROS) levels in wild-type but not FXR(-/-) mouse hepatocytes. FXR knockdown abolished the inhibition of 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]-Benzoic acid (GW4064) on JNK phosphorylation and ROS production induced by H₂O₂in HepG2 cells. The gene expression of SOD3, an antioxidant defense enzyme, was increased by FXR activation in vitro and in vivo. An FXR-responsive element, inverted repeat separated by 1 nucleotide in SOD3 promoter, was identified by a combination of transcriptional reporter assays, EMSAs, and chromatin immunoprecipitation assays, which indicated that SOD3 could be a direct FXR target gene. SOD3 knockdown abolished the inhibition of GW4064 on JNK phosphorylation induced by H₂O₂in HepG2 cells. In summary, FXR may regulate SOD3 expression to suppress ROS production, resulting in decreasing JNK activity. These results suggest that FXR, as a novel JNK suppressor, may be an attractive therapeutic target for liver cancer treatment.
authors.affiliation: State Key Laboratory of Chemical Resource Engineering (Y.-D.W., C.G., X.L.), College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, People's Republic of China; Pathogenic Organisms and Immunology Lab (W.-D.C., C.L.), School of basic medical science, Inner Mongolia Medical University, Hohhot, 010110, Inner Mongolia, People's Republic of China; Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery (W.D.C., Y.L., H.Q., H.S., J.K.), School of Medicine, Henan University, Kaifeng, 475004, Henan, People's Republic of China; and Division of Molecular Diabetes Research (F.Y., X.W., W.H.), Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 91010.
authors.forename: Yan-Dong
authors.initials: YD
authors.lastname: Wang
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Chen
authors.forename: Cunbao
authors.initials: C
authors.lastname: Li
authors.forename: Cong
authors.initials: C
authors.lastname: Guo
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Qi
authors.forename: Hailing
authors.initials: H
authors.lastname: Shen
authors.forename: Jing
authors.initials: J
authors.lastname: Kong
authors.forename: Xuecheng
authors.initials: X
authors.lastname: Long
authors.forename: Frank
authors.initials: F
authors.lastname: Yuan
authors.forename: Xichun
authors.initials: X
authors.lastname: Wang
authors.forename: Wendong
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001483:Base Sequence; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016877:Oxidants / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000975:Antioxidants; D007555:Isoxazoles; D048031:JNK Mitogen-Activated Protein Kinases; D016877:Oxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D013482:Superoxide Dismutase; D000099150:Receptor, Farnesoid X-Activated; C441642:SOD3 protein, human; C499090:Sod3 protein, mouse; C412815:GW 4064