Commonality of the gene programs induced by effectors of apoptosis in androgen-dependent and -independent prostate cells.

Prostate tissue is composed of both androgen-dependent and -independent cells. To identify the gene program induced by effectors of apoptosis in both of these cell types, we performed differential hybridization on a complementary DNA library prepared from an androgen-independent prostate cancer cell line, AT-3, exposed to ionomycin. Five distinct complementary DNAs representing ionomycin-inducible genes, designated prostate apoptosis response (par) -1, -2, -3, -4, and -5, were identified. Nucleotide sequencing identified par-1 as the rat homologue of a serum- and oxidative stress-inducible gene, 3CH134/erp/CL100; par-2 as the injury-inducible gene HB-EGF encoding a heparin-binding epidermal growth factor-like growth factor; par-3 as the serum-inducible gene cyr-61; whereas par-4 and par-5 were novel, as judged by a GenBank search. par-1, -3, -4, and -5 were also induced in rat ventral prostate following castration, which causes androgen ablation, leading to apoptosis of androgen-dependent prostate cells. Pretreatment of rats with nifedipine prior to castration abrogated inducible expression of the par genes, indicating that their expression was downstream to Ca2+ elevation. Further characterization of these genes revealed that induction of par-4 is apoptosis specific: it is not induced by effectors of growth stimulation, oxidative stress and necrosis, or growth arrest in prostate cells. Together, par-1, -3, -4, and -5 represent an apoptosis response gene program common to both androgen-dependent and -independent prostate cells. Thus, cell death programs in prostate cells are comprised of genes specifically associated with apoptosis as well as those with multifunctional roles in growth regulation. Since elevation of intracellular Ca2+ is central to apoptosis in many cell types, we predict that par genes will be important components of diverse effector-driven apoptotic pathways.