Antimycin A sensitizes cells to TRAIL-induced apoptosis through upregulation of DR5 and downregulation of c-FLIP and Bcl-2
- Antimycin A sensitizes cells to TRAIL-induced apoptosis through upregulation of DR5 and downregulation of c-FLIP and Bcl-2
- 이태진; 이성준; 김은애; 송경섭[송경섭]; 김민재; 권택규[권택규]; 이대형
- MITOCHONDRIAL PERMEABILITY TRANSITION; DEATH RECEPTOR 5; REACTIVE OXYGEN; MEDIATED APOPTOSIS; CANCER-CELLS; RESPIRATORY-CHAIN; CYTOCHROME-C; SUPEROXIDE; INHIBITION; ACTIVATION
- Issue Date
- SPANDIDOS PUBL LTD
- INTERNATIONAL JOURNAL OF ONCOLOGY, v.41, no.4, pp.1425 - 1430
- 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.
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