title: YM155 sensitizes TRAIL-induced apoptosis through cathepsin S-dependent down-regulation of Mcl-1 and NF-κB-mediated down-regulation of c-FLIP expression in human renal carcinoma Caki cells.
abstract: YM155, a small-molecule survivin inhibitor, has been reported for its anti-cancer activity in various cancer cells. In this study, we investigated the effect of YM155 to enhance TRAIL-mediated apoptosis in human renal carcinoma cells. We found that YM155 alone had no effect on apoptosis, however, combined treatment with YM155 and TRAIL markedly induced apoptosis in human renal carcinoma cells (Caki, ACHN, and A498), breast cancer cells (MDA-MB231), and glioma cells (U251MG), but not normal cells [mesangial cell (MC) and human skin fibroblast (HSF)]. YM155 induced down-regulation of Mcl-1 expression at the post-translational levels, and the overexpression of Mcl-1 markedly inhibited YM155 plus TRAIL-induced apoptosis. Furthermore, YM155 induced down-regulation of c-FLIP mRNA expression through inhibition of NF-κB transcriptional activity. Ectopic expression of c-FLIP markedly blocked YM155-induced TRAIL sensitization. Taken together, our results suggested that YM155 sensitizes TRAIL-mediated apoptosis via down-regulation of Mcl-1 and c-FLIP expression in renal carcinoma Caki cells.
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu 704-701, South Korea.
authors.forename: Seon Min
authors.initials: SM
authors.lastname: Woo
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu 704-701, South Korea.
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Min
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu 704-701, South Korea.
authors.forename: Bo Ram
authors.initials: BR
authors.lastname: Seo
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu 704-701, South Korea.
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors; D007680:Kidney Neoplasms / Q000188:drug therapy*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: C107489:BIRC5 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009285:Naphthoquinones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D002403:Cathepsins; C028217:cathepsin S; C523798:sepantronium
keywords: Mcl-1; TRAIL; YM155; c-FLIP; lysosome