Despite distinct dissimilarities, diverse cancers express several common pro-tumorigenic traits. We present here evidence that the pro-apoptotic protein Par-4 utilizes one such common tumorigenic trait to become selectively activated and induce apoptosis in cancer cells. Elevated PKA activity noted in cancer cells activated the apoptotic function of ectopic Par-4 or its SAC domain, which induces apoptosis selectively in cancer cells and not in normal or immortalized cells. PKA preferentially phosphorylated Par-4 at the T155 residue within the SAC domain in cancer cells. Moreover, pharmacological-, peptide- or siRNA-mediated inhibition of PKA activity in cancer cells resulted in abrogation of both T155 phosphorylation and apoptosis by Par-4. The mechanism of activation of endogenous Par-4 was similar to that of ectopic Par-4, and in response to exogenous stimuli, endogenous Par-4 induced apoptosis by a PKA and phospho-T155 dependent mechanism. Enforced elevation of PKA activity in normal cells resulted in apoptosis by the SAC domain of Par-4 in a T155-dependent manner. Together, these observations suggest that selective apoptosis of cancer cells by the SAC domain of Par-4 involves phosphorylation of T155 by PKA. These findings uncover a novel mechanism engaging PKA, a pro-cancerous activity commonly elevated in most tumor cells, to activate the cancer selective apoptotic action of Par-4.
| Identifer | oai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:gradschool_diss-1474 |
| Date | 01 January 2005 |
| Creators | Gurumurthy, Sushma |
| Publisher | UKnowledge |
| Source Sets | University of Kentucky |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | University of Kentucky Doctoral Dissertations |
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