title: Antimycin A sensitizes cells to TRAIL-induced apoptosis through upregulation of DR5 and downregulation of c-FLIP and Bcl-2.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been the focus as a potential anticancer drug, because it induces apoptosis in a wide variety of cancer cells but not in most normal human cell types. In this study, we showed that combination treatment with sub-toxic doses of antimycin A (AMA), an inhibitor of electron transport, plus TRAIL induced apoptosis in human renal cancer cells, but not in normal tubular kidney cells. Treatment of Caki cells with AMA upregulated the death receptor 5 (DR5) protein and downregulated c-FLIP and Bcl-2 proteins in a dose-dependent manner. AMA-induced decrease of c-FLIPL and c-FLIPs protein levels which were caused by increased protein instability, which was confirmed by the result showing that treatment with a protein biosynthesis inhibitor, CHX, accelerated degradation of c-FLIPL and c-FLIPs proteins caused by AMA treatment. We also found that AMA induced upregulation of DR5 and downregulation of Bcl-2 at the transcriptional level. Pretreatment with N-acetyl-l-cysteine (NAC) partly recovered the expression levels of c-FLIPL and c-FLIPs proteins were downregulated by the AMA treatment, suggesting that AMA appears to be partially dependent on the generation of ROS for downregulation of c-FLIPL and c-FLIPs. Collectively, this study demonstrates that AMA enhances TRAIL-induced apoptosis in human renal cancer cells by upregulation of DR5 as well as downregulation of c-FLIP and Bcl-2. Furthermore, this study shows that AMA markedly increases sensitivity to cisplatin in Caki human renal cancer cells.
authors: Department of Anatomy, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
authors: Sung-Jun
authors: SJ
authors: Lee
authors: Eun-Ae
authors: EA
authors: Kim
authors: Kyoung Seob
authors: KS
authors: Song
authors: Min-Jae
authors: MJ
authors: Kim
authors: Dae Hyung
authors: DH
authors: Lee
authors: Taeg Kyu
authors: TK
authors: Kwon
authors: Tae-Jin
authors: TJ
authors: Lee
mesh_terms: D000968:Antimycin A / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2 / Q000235:genetics*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D000968:Antimycin A