Prostate cancer is the second most common cause of cancer death in men in the United States. The only treatment for advanced disease is hormonal therapy, which is not curative. Hormonal therapy is severely limited because androgen-dependent tumor typically becomes androgen independent Although there has been a considerable amount of work on the regulation of prostatic cell growth by androgen and the molecular events following androgen withdrawal, relatively little is known about the receptors expressed by androgen-independent prostate carcinoma cells. We have been working on new approaches to the treatment of this neoplasm through identification of novel cell surface receptors that transmit a growth inhibitory signal through activation of the phosphatidyhnositol signal through activation of the phosphatidylinositol signal transduction pathway and mobilization of intracellular Ca(2+). Twelve hormones and neurotransmitters stimulated an increase in cytoplasmic free Ca(2+) in human androgren-independent prostate carcinoma cell lines. Stimulation of the plasma membrane receptor for adenine nucleotides, the P2 purinergic receptor, consistently caused a massive increase in Ca(2+) release, close to the total intracellular releasable Ca(2+). Studies with Ca(2+) channel blockers and EGTA demonstrated that this response derived approximately 50% from release from internal stores and 50% from the opening of dihydropyridine-sensitive plasma membrane Ca(2+) channels. High pressure liquid chromatographic analysis of inositol phosphate isomers showed a purinoceptor-linked increase in phosphatidylinositol turnover. Treatment with ATP or the non-hydrolyzable analog adenyhmidodiphosphate induced a marked change in cell morphology, including chromatin condensation and nucleolar degeneration, and significantly inhibited cell growth in vitro. Normal prostatic cells are triggered to undergo programmed cell death in response to androgen withdrawal. This response can be inhibited by Ca(2+) channel blockers. Our data suggest that it may be possible to circumvent the absence of androgen receptors in androgen-independent prostate carcinoma cells, and trigger a cytotoxic response through activation of a Ca(2+) dependent signal.
