title: Transcriptional and post-translational regulation of Bim controls apoptosis in melatonin-treated human renal cancer Caki cells.
abstract: Melatonin (N-acetyl-5-methoxytryptamine) has recently gained attention as an anticancer agent and for combined cancer therapy. In this study, we investigated the underlying molecular mechanisms of the effects of melatonin on cancer cell death. Treatment with melatonin induced apoptosis and upregulated the expression of the pro-apoptotic protein Bcl-2-interacting mediator of cell death (Bim) in renal cancer Caki cells. Furthermore, downregulation of Bim expression by siRNA markedly reduced melatonin-mediated apoptosis. Melatonin increased Bim mRNA expression through the induction of Sp1 and E2F1 expression and transcriptional activity. We found that melatonin also modulated Bim protein stability through the inhibition of proteasome activity. However, melatonin-induced Bim upregulation was independent of melatonin's antioxidant properties and the melatonin receptor. Taken together, our results suggest that melatonin induces apoptosis through the upregulation of Bim expression at the transcriptional level and at the post-translational level.
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu, Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Seon Min
authors.initials: SM
authors.lastname: Woo
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Min
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D008550:Melatonin
keywords: Bim; apoptosis; melatonin; proteasome activity; transcriptional regulation