Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in cancer prevention and have been shown to suppress the formation of colorectal tumors in both humans and rodents. The chemopreventive action of NSAIDs is believed to be mediated through induction of apoptosis in preneoplastic cells. However, the precise molecular mechanisms of NSAID-induced apoptosis remain unclear. Previous studies demonstrated that second mitochondria-derived activator of caspase (SMAC) plays an important role in executing NSAID-induced apoptosis in colon cancer cells. SMAC-knockout HCT116 colon cancer cells are resistant to NSAID-induced apoptosis, and are deficient in caspase activation and cytosolic release of cytochrome c and apoptosis inducing factor (AIF). In this study, we tested the hypothesis that SMAC regulates the release of cytochrome c and activation of caspase cascade through a feed-back amplification loop. We found that the N-terminal AVPI domain of SMAC is required for the proapoptotic activity of SMAC. Following NSAID treatment, SMAC promotes dissociation of caspase-3 from inhibitor of apoptosis proteins (IAPs), which in turn leads to mitochondrial dysfunction. We also studied the effects of pharmacological manipulation on NSAID-induced apoptosis by employing small-molecule compounds that functionally mimic the AVPI domain of SMAC. A synergistic action of NSAIDs and SMAC mimetics was observed in inducing a robust apoptotic response in several colon cancer cell lines, as well as in NSAID-resistant BAX-KO and SMAC-KO cell lines. SMAC mimetics appear to potentiate NSAID-induced apoptosis by stimulating the release of cytochrome c from mitochondria and activation of caspases. Together, these results suggest that SMAC may be useful as a target for the development of more effective chemopreventive agents.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-05262008-202753 |
| Date | 02 September 2008 |
| Creators | Bank, Alex |
| Contributors | Xiao-Ming Yin, Yu Jiang, Daniel E. Johnson, Robert W. Sobol, Jr., Lin Zhang |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-05262008-202753/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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