Androgen-ablation is standard therapy for prostate cancer, but this therapy is rarely curative because the cancer within an individual patient contains both androgen-dependent and - independent cells. Several studies have shown an increase in the anti-apoptotic protein Bcl-2 in hormone-independent recurrent prostate cancer, and suggested that groups of prostate cancer cells may resist apoptosis after androgen withdrawal owing to expression of Bcl-2 protein. Approaches to identify novel treatments for recurrent prostate cancer, therefore, should include the development of various strategies that will enable down- regulation of Bcl-2 expression. Our recent studies have identified a novel pro-apoptotic protein designated Prostate Apoptosis Response-4 (Par-4) that can sensitize both androgen-dependent and -independent cells to apoptosis. Most importantly, our preliminary studies suggest that Par-4 down-regulates Bcl-2 protein expression. A goal of this project is to understand the relationship between Par-4 and Bcl-2 expression in androgen-dependent and -independent prostate cancer cell lines, and in tumor specimens representing primary, metastatic, or recurrent prostate cancers.
Three specific aims are proposed in this project.
Aim I will address the mechanism by which Par-4 down-regulates Bcl-2. Specifically, we will test whether Par-4 causes transcriptional repression of the bcl-2 promoter; and if so, further identify the cis elements in the bcl-2 promoter that mediate the repression.
Aim II will examine the functional relevance of Par-4 mediated bcl-2-down-regulation in prostate cancer cells. Finally, Aim III will address the expression of Par-4 and Bcl-2 in hormone-dependent and -independent prostate cancer specimens from patients. We will use qualitative and quantitative approaches to determine whether Par-4 and Bcl-2 expression is inversely related in advanced, metastatic, or recurrent prostate tumors. Together, these studies will enable us to examine the functional link between the pro- apoptotic protein Par-4 and a key cell survival protein Bcl-2, and help design strategies for control of recurrent prostate tumors. Because Bcl-2 blocks diverse insult-induced apoptotic pathways and thereby confers resistance to anti-cancer therapy, the findings of this study can be extended to facilitate apoptosis with Par-4 in diverse cancer model systems.
| Pang, Allan H; Obiero, Josiah M; Kulczyk, Arkadiusz W et al. (2018) A crystal structure of coil 1B of vimentin in the filamentous form provides a model of a high-order assembly of a vimentin filament. FEBS J 285:2888-2899 |
| Sviripa, Vitaliy M; Burikhanov, Ravshan; Obiero, Josiah M et al. (2016) Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin. Org Biomol Chem 14:74-84 |
| de Thonel, A; Hazoumé, A; Kochin, V et al. (2014) Regulation of the proapoptotic functions of prostate apoptosis response-4 (Par-4) by casein kinase 2 in prostate cancer cells. Cell Death Dis 5:e1016 |
| Burikhanov, Ravshan; Sviripa, Vitaliy M; Hebbar, Nikhil et al. (2014) Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis. Nat Chem Biol 10:924-926 |
| Liu, Yinxing; Gilbert, Misty R; Kyprianou, Natasha et al. (2014) The tumor suppressor prostate apoptosis response-4 (Par-4) is regulated by mutant IDH1 and kills glioma stem cells. Acta Neuropathol 128:723-32 |
| Hebbar, Nikhil; Shrestha-Bhattarai, Tripti; Rangnekar, Vivek M (2014) Cancer-selective apoptosis by tumor suppressor par-4. Adv Exp Med Biol 818:155-66 |
| Burikhanov, Ravshan; Shrestha-Bhattarai, Tripti; Hebbar, Nikhil et al. (2014) Paracrine apoptotic effect of p53 mediated by tumor suppressor Par-4. Cell Rep 6:271-7 |
| Hebbar, Nikhil; Shrestha-Bhattarai, Tripti; Rangnekar, Vivek M (2013) Par-4 prevents breast cancer recurrence. Breast Cancer Res 15:314 |
| Shrestha-Bhattarai, Tripti; Hebbar, Nikhil; Rangnekar, Vivek M (2013) Par(-4)oxysm in breast cancer. Cancer Cell 24:3-5 |
| Burikhanov, Ravshan; Shrestha-Bhattarai, Tripti; Qiu, Shirley et al. (2013) Novel mechanism of apoptosis resistance in cancer mediated by extracellular PAR-4. Cancer Res 73:1011-9 |
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