Biomol Ther.
2013 Jan;21(1):29-34.
Down-Regulation of Survivin by Nemadipine-A Sensitizes Cancer Cells to TRAIL-Induced Apoptosis
- Affiliations
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- 1Ilsong Institute for Life Science, Hallym University, Anyang 431-060, Republic of Korea.
- 2Graduate School of East-West Medical Science, Kyung Hee University, Yongin 446-701, Republic of Korea. dhcho@khu.ac.kr ik.kim@amc.seoul.kr
- 3Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Science, Seoul 136-706, Republic of Korea.
- 4Asan Institute for Life Science, Asan Medical Center, Seoul 138-736, Republic of Korea. dhcho@khu.ac.kr ik.kim@amc.seoul.kr
- 5Institute for Innovative Cancer Research, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea.
- 6Department of Bioinformatics and Life Science, Soongsil University, Seoul 156-743, Republic of Korea.
- 7Department of Medicine, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Abstract
- The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines. TRAIL selectively induces apoptotic cell death in various tumors and cancer cells, but it has little or no toxicity in normal cells. Agonism of TRAIL receptors has been considered to be a valuable cancer-therapeutic strategy. However, more than 85% of primary tumors are resistant to TRAIL, emphasizing the importance of investigating how to overcome TRAIL resistance. In this report, we have found that nemadipine-A, a cell-permeable L-type calcium channel inhibitor, sensitizes TRAIL-resistant cancer cells to this ligand. Combination treatments using TRAIL with nemadipine-A synergistically induced both the caspase cascade and apoptotic cell death, which were blocked by a pan caspase inhibitor (zVAD) but not by autophagy or a necrosis inhibitor. We further found that nemadipine-A, either alone or in combination with TRAIL, notably reduced the expression of survivin, an inhibitor of the apoptosis protein (IAP) family of proteins. Depletion of survivin by small RNA interference (siRNA) resulted in increased cell death and caspase activation by TRAIL treatment. These results suggest that nemadipine-A potentiates TRAIL-induced apoptosis by down-regulation of survivin expression in TRAIL resistant cells. Thus, combination of TRAIL with nemadipine-A may serve a new therapeutic scheme for the treatment of TRAIL resistant cancer cells, suggesting that a detailed study of this combination would be useful.
Keyword
MeSH Terms
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Apoptosis*
Autophagy
Calcium Channels, L-Type
Cell Death
Cytokines
Down-Regulation*
Felodipine
Humans
Necrosis
Receptors, TNF-Related Apoptosis-Inducing Ligand
RNA Interference
Tumor Necrosis Factor-alpha
Calcium Channels, L-Type
Cytokines
Felodipine
Receptors, TNF-Related Apoptosis-Inducing Ligand
Tumor Necrosis Factor-alpha
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