title: Adiponectin induces apoptosis in hepatocellular carcinoma through differential modulation of thioredoxin proteins.
abstract: Adiponectin blocks hepatocellular carcinoma (HCC) progression by inducing cell apoptosis through the modulation of C-Jun N-terminal kinase and mammalian target of rapamycin. However, the precise upstream signaling pathways or molecules remain elusive. In the present study, we analyzed the role of antioxidant protein thioredoxin (Trx) in adiponectin-induced apoptosis in HCC. Adiponectin treatment decreased the viabilities of both HepG2 and Huh7 HCC cells accompanied by increased accumulation of intracellular reactive oxygen species, as evidenced by 2',7'-dichlorodihydrofluorescein diacetate staining. Pretreatment of these cells with the deoxidant N-acetylcysteine blocked the inhibitory effect of adiponectin. Levels of Trx2 protein in both HCC cells were significantly decreased, and the level of Trx1 was significantly inhibited in Huh7 cells while unchanged in HepG2 cells. However, the redox state of Trx1 was altered from reduced to the oxidized form following adiponectin treatment in HepG2 cells. Overexpression of both Trx proteins rescued adiponectin-induced cell apoptosis, whereas mutated Trx proteins were less effective. Further analysis suggested that both ASK1 and JNK signaling are involved in this process. Trx1 and Trx2 proteins also manifested protective effects on HCC cells in response to adiponectin treatment in a xenograft tumor model. Furthermore, high levels of Trx proteins and low adiponectin expression levels were found in primary human HCC samples compared with paracancerous tissues. These results suggest that Trx proteins play important roles in mediating adiponectin-induced HCC cell apoptosis, thus providing new insights into the pathogenesis of HCC and identifying adiponectin and Trx proteins as potential combinational therapeutic targets for the treatment of HCC.
authors.affiliation: Department of Neurobiology, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, Beijing 100069, China.
authors.forename: Su-Qian
authors.initials: SQ
authors.lastname: Xing
authors.affiliation: Department of Medical Genetics, Capital Medical University, Beijing 100069, China.
authors.forename: Chen-Guang
authors.initials: CG
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, Beijing 100069, China; Animal Experimental Center of PLA General Hospital, Beijing 100853, China.
authors.forename: Ji-Fang
authors.initials: JF
authors.lastname: Yuan
authors.affiliation: Department of Neurobiology, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, Beijing 100069, China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Yang
authors.affiliation: School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
authors.forename: Shu-Dong
authors.initials: SD
authors.lastname: Zhao
authors.affiliation: Department of Neurobiology, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, Beijing 100069, China. Electronic address: hzhang@ccmu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D052242:Adiponectin / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D052242:Adiponectin; D013879:Thioredoxins
keywords: Adiponectin; Apoptosis; Hepatocellular carcinoma; Thioredoxin