MECHANISM OF CANCER SELECTIVE APOPTOSIS BY PAR-4

Author

Sushma Gurumurthy, University of KentuckyFollow

Date Available

12-14-2011

Year of Publication

2005

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Graduate School

Department/School/Program

Toxicology

Faculty

Dr. Vivek . M. Rangnekar

Abstract

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.

Recommended Citation

Gurumurthy, Sushma, "MECHANISM OF CANCER SELECTIVE APOPTOSIS BY PAR-4" (2005). University of Kentucky Doctoral Dissertations. 471.
https://uknowledge.uky.edu/gradschool_diss/471