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.