Bank, Alex
(2008)
The Role of SMAC in NSAID-induced Apoptosis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
2 September 2008 |
| Date Type: |
Completion |
| Defense Date: |
21 May 2008 |
| Approval Date: |
2 September 2008 |
| Submission Date: |
26 May 2008 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Pharmacology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
apoptosis; NSAID; SMAC; SMAC mimetics; cancer; colon cancer |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-05262008-202753/, etd-05262008-202753 |
| Date Deposited: |
10 Nov 2011 19:45 |
| Last Modified: |
19 Dec 2016 14:36 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/7954 |
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