Androgen-ablation is standard therapy for metastatic prostate cancer because 80% patients show an initial response to such a treatment. However, this therapy is rarely curative because metastatic cancer within an individual patient is heterogeneous, including both androgen-dependent and -independent prostatic cancer cells even before therapy is initiated. Elevation of intracellular Ca2+ levels following androgen-ablation seems necessary for apoptosis in prostatic cells. Androgen-ablation does not induce elevated intracellular Ca2+ levels in the androgen-independent cells presumably due to a block in the proximal events. However, elevation of intracellular Ca2+ by ionomycin can cause apoptosis in the androgen-independent Dunning R-3327 AT-3 rat prostatic cancer cells, suggesting that events downstream of Ca2+ elevation may be common to the apoptotic process in androgen-dependent cells subjected to androgen- ablation and androgen-independent cells exposed to ionomycin. By differential hybridization and Northern analysis, we have identified a common set of genes induced in both androgen-dependent and -independent cells. One of these genes, designated prostate apoptosis-response-4 (par- 4) was found to be induced only by effectors of apoptosis and not by growth-stimulatory, growth arrest, or oxidative stress signals. We hypothesize that par-4 is an apoptosis-response-specific gene, and is likely to be functionally involved in apoptosis. The function of par-4 in ionomycin-driven apoptosis in AT-3 cells will be determined by performing transfection studies with appropriate constructs for antisense inhibition or overexpression of this gene. We will ascertain that in prostate cells parA induction is apoptosis-response-specific, by determining whether this gene is inducible by androgen in rat ventral prostate. Moreover, we will study par-4 expression in diverse in vitro experimental model systems for apoptosis, growth stimulation, growth arrest, differentiation, and stress, to determine whether par-4 induction is apoptosis-specific. We have already shown that par-4 is a novel gene as judged by GenBank search, and that induction of this gene after androgen-ablation in rat ventral prostate is downstream of intracellular Ca2+ levels. This study will be the first step in the direction of delineating Ca2+-driven apoptotic pathways. A cell death-specific gene will be useful clinically as a marker for involution of the prostate and as a candidate for gene therapy of androgen-dependent and androgen- independent prostatic-tumors.
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