Journal
CANCER RESEARCH
Volume 68, Issue 1, Pages 276-284Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-5242
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Funding
- NATIONAL CANCER INSTITUTE [R01CA121105, R01CA106348] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008424] Funding Source: NIH RePORTER
- NCI NIH HHS [CA121105, CA106348, R01 CA106348] Funding Source: Medline
- NIGMS NIH HHS [T32GM08424] Funding Source: Medline
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Nonsteroidal anti-inflammatory drugs (NSAID) are effective in suppressing the formation of colorectal tumors. However, the mechanisms underlying the antineoplastic effects of NSAIDs remain unclear. The effects of NSAIDs are incomplete, and resistance to NSAIDs is often developed. Growing evidence has indicated that the chemopreventive activity of NSAIDS is mediated by induction of apoptosis. Our previous studies showed that second mitochondria-derived activator of caspase (SMAC)/Diablo, a mitochondrial apoptogenic protein, plays an essential role in NSAID-induced apoptosis in colon cancer cells. In this study, we found that SMAC mediates NSAID-induced apoptosis through a feedback amplification mechanism involving interactions with inhibitor of apoptosis proteins, activation of caspase-3, and induction of cytosolic release of cytochrome c. Small-molecule SMAC mimetics at nanomolar concentrations significantly sensitize colon cancer cells to NSAID-induced apoptosis by promoting caspase-3 activation and cytochrome c release. Furthermore, SMAC mimetics overcome NSAID resistance in Bax-deficient or SMAC-deficient colon cancer cells by restoring caspase-3 activation and cytochrome c release. Together, these results suggest that SMAC is useful as a target for the development of more effective chemopreventive strategies and agents.
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