title: Sodium arsenite down-regulates the expression of X-linked inhibitor of apoptosis protein via translational and post-translational mechanisms in hepatocellular carcinoma.
abstract: X-linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitors of apoptosis protein (IAP) family, and has been reported to exhibit elevated expression levels in hepatocellular carcinoma (HCC) and promote cell survival, metastasis and tumor recurrence. Targeting XIAP has proven effective for the inhibition of cancer cell proliferation and restoration of cancer cell chemosensitivity. Arsenic (or sodium arsenite) is a potent anti-tumor agent used to treat patients with acute promyelocytic leukemia (APL). Additionally, arsenic induces cell growth inhibition, cell cycle arrest and apoptosis in human HCC cells. In this study, we identified XIAP as a target for sodium arsenite-induced cytotoxicity in HCC. The exposure of HCC cell lines to sodium arsenite resulted in inhibition of XIAP expression in both a dose- and time-dependent manner. Sodium arsenite blocked the de novo XIAP synthesis and the activity of its internal ribosome entry site (IRES) element. Moreover, treatment with sodium arsenite decreased the protein stability of XIAP and induced its ubiquitin-proteasomal degradation. Overexpression of XIAP attenuated the pro-apoptotic effect of sodium arsenite in HCC. Taken together, our data demonstrate that sodium arsenite suppresses XIAP expression via translational and post-translational mechanisms in HCC.
authors.affiliation: Gene Research Center, Shanghai Medical College, Fudan University, Shanghai 200032, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Hao
authors.forename: Lijing
authors.initials: L
authors.lastname: Wang
authors.forename: Dongwei
authors.initials: D
authors.lastname: Jia
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ruan
authors.forename: Jianxin
authors.initials: J
authors.lastname: Gu
mesh_terms: D018053:Arsenites / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D012270:Ribosomes / Q000187:drug effects*; D017670:Sodium Compounds / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018053:Arsenites; D004791:Enzyme Inhibitors; D017670:Sodium Compounds; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C017947:sodium arsenite