Antimycin A sensitizes cells to TRAIL-induced apoptosis through upregulation of DR5 and downregulation of c-FLIP and Bcl-2

Lee,Sung-Jun; Kim,Eun-Ae; Song,Kyoung  Seob; Kim,Min-Jae; Lee,Dae   Hyung; Kwon,Taeg  Kyu; Lee,Tae-Jin

doi:10.3892/ijo.2012.1575

Antimycin A sensitizes cells to TRAIL-induced apoptosis through upregulation of DR5 and downregulation of c-FLIP and Bcl-2

Authors:
- Sung-Jun Lee
- Eun-Ae Kim
- Kyoung Seob Song
- Min-Jae Kim
- Dae Hyung Lee
- Taeg Kyu Kwon
- Tae-Jin Lee
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Affiliations: Department of Anatomy, College of Medicine, Yeungnam University, Daegu, Republic of Korea, Department of Physiology, College of Medicine, Kosin University, Busan, Republic of Korea, Department of Obstetrics and Gynecology, Yeungnam University, Daegu, Republic of Korea, Department of Immunology, School of Medicine, Keimyung University, Daegu, Republic of Korea
Published online on: July 27, 2012 https://doi.org/10.3892/ijo.2012.1575
Pages: 1425-1430

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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.

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