title: IKKβ downregulation is critical for triggering JNKs-dependent cell apoptotic response in the human hepatoma cells under arsenite exposure.
abstract: Arsenite has a long history in treating leukemia, which might be also effective in the therapy of other cancers. Our previous published data have demonstrated that arsenite exposure induces apoptosis in the HepG2 human hepatoma cells via activating JNKs/AP-1 pathway, but the upstream signaling events responsible for JNKs (c-Jun N-terminal kinase) cascade activation have not been fully discovered. Since cross-talk between IKK/NF-κB and JNKs pathways under stress conditions is a hot topic, in this article, we investigate the potential roles of IKKα and IKKβ, the catalytic subunits of IKK complexes, in the arsenite-induced JNKs pathway activation in the HepG2 cells. We found that arsenite exposure induced JNKs and AP-1 activation accompanying with a significant reduction of both IKKα and IKKβ expressions. Overexpression of IKKβ, but not of IKKα, inhibited arsenite-induced MKK7/JNKs/AP-1 pathway activation as well as the apoptotic response. Therefore,  we conclude that the downregulation of IKKβ expression is the prerequisite signaling event for mediating JNKs pathway activation and the cellular apoptotic response in the HepG2 cells under arsenite exposure. Targeting IKKβ might be helpful to enhance the tumor therapeutic effect of arsenite.
authors.affiliation: Department of Cellular Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Hao
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.forename: Wen
authors.initials: W
authors.lastname: Dong
authors.forename: Meiru
authors.initials: M
authors.lastname: Hu
authors.forename: Shengtao
authors.initials: S
authors.lastname: Yuan
authors.forename: Lun
authors.initials: L
authors.lastname: Song
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D018053:Arsenites; D018808:Transcription Factor AP-1; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; C015001:arsenite