Sulindac Sulfide Differentially Induces Apoptosis in Smac-Proficient and -Deficient Human Colon Cancer Cells
| Autor: | Jingxue Shi, Jie An, M. Saeed Sheikh, Qin He, Ying Huang, Hong Sun |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Sulindac
biology business.industry Cytochrome c Pharmaceutical Science Mitochondrion Pharmacology Article digestive system diseases Downregulation and upregulation Apoptosis biology.protein medicine Cancer research biological phenomena cell phenomena and immunity Signal transduction Receptor business Molecular Biology Caspase medicine.drug |
| Zdroj: | Molecular and Cellular Pharmacology. 1:92-97 |
| ISSN: | 1938-1247 |
| Popis: | Sulindac, the non-steroidal anti-inflammatory drug has shown promise in the prevention of colon cancer but the molecular mechanisms by which it mediates such effects remain to be elucidated. Sulindac sulfide is the major active metabolite of sulindac and believed to be responsible for mediating the effects of sulindac. Previously, our group and others have shown that sulindac sulfide induces apoptosis by engaging death receptor and mitochondrial pathways and that a cross-talk exists between these two pathways during sulindac sulfide-induced apoptosis. Second mitochondrial-derived activator (Smac) is an important pro-apoptotic molecule that activates caspases by antagonizing the inhibitors of apoptosis (IAPs). In this study, we have utilized Smac-proficient and -deficient human colon cancer cells to investigate the role of Smac during sulindac sulfide-induced apoptosis and found that Smac deficiency affects sulindac sulfide-induced apoptosis in human colon cancer cells. Sulindac sulfide-induced apoptosis is coupled with upregulation of death receptor 5 (DR5), and activation of caspases 3, 9 and 8 in Smac-proficient cells. In Smac-deficient cells, although sulindac sulfide-induced DR5 upregulation is not altered, activation of caspases 3, 9 and 8 is affected. Smac deficiency also abrogates sulindac sulfide-induced cytochrome c release from mitochondria into cytosol. Our results, therefore, demonstrate that Smac is involved in sulindac sulfide-induced apoptotic signal transduction in human colon cancer cells and highlight the existence of a potential cross-talk between Smac and cytochrome c. |
| Databáze: | OpenAIRE |
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