title: Synergistic induction of TRAIL-mediated apoptosis by anisomycin in human hepatoma cells via the BH3-only protein Bid and c-Jun/AP-1 signaling pathway.
abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF super-family, and it has been shown that many human cancer cell lines are refractory to TRAIL-induced cell death. However, the molecular mechanisms underlying resistance are unclear. In the present study, we show that TRAIL-resistance is reversed in human hepatoma cells by anisomycin, which is known to inhibit protein synthesis and induce ribotoxic stress. Synergistic induction of apoptosis in cells treated with anisomycin plus TRAIL was associated with activation of caspases and cleavage of Bid, a pro-apoptotic BH3-only protein. Silencing of Bid expression by small interfering RNA (siRNA) significantly attenuated the loss of mitochondrial membrane potential (MMP, Δψm) and significantly increased induction of apoptosis in cells treated with anisomycin and TRAIL, confirming that Bid cleavage is required for the response. In addition, c-Jun/AP-1 was rapidly activated upon stimulation with anisomycin; however, the knockdown of c-Jun/AP-1 expression by c-Jun siRNA markedly reduced anisomycin plus TRAIL-induced loss of MMP and apoptosis. Taken together, the findings show that anisomycin sensitizes TRAIL-mediated hepatoma cell apoptosis via the mitochondria-associated pathway, involving the cleavage of Bid and activation of the c-Jun/AP-1 pathway, indicating that this compound can be used as an anti-tumor agent in combination with TRAIL.
authors.affiliation: School of Pharmaceutical Science, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Cheng-Yun
authors.initials: CY
authors.lastname: Jin
authors.forename: Cheol
authors.initials: C
authors.lastname: Park
authors.forename: Su Hyun
authors.initials: SH
authors.lastname: Hong
authors.forename: Min Ho
authors.initials: MH
authors.lastname: Han
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Jeong
authors.forename: HongDe
authors.initials: H
authors.lastname: Xu
authors.forename: HongMin
authors.initials: H
authors.lastname: Liu
authors.forename: Gi Young
authors.initials: GY
authors.lastname: Kim
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
mesh_terms: D000841:Anisomycin / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D011500:Protein Synthesis Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D018808:Transcription Factor AP-1; D000841:Anisomycin