The growth and progression of prostate cancer in men is a common clinical condition and, failing a response to androgen ablation, few affective treatments have been developed. Much recent attention has focused on the actions of non-steroidal factors and the regulation of prostate epithelial cell proliferation. We and others have reported that activin is a potent growth inhibitor of the androgen-dependent human prostate cancer cell line LNCaP, capable of rapidly reducing cell proliferation and inducing apoptosis. In contrast, the androgen-independent human prostate cancer cell line PC-3 is resistant to activin. Despite this difference in phenotype, both cell lines express the mRNAs for activin receptors and the activin binding protein follistatin (which binds to and inactivates activin). In summary, these data suggest that a spectrum of activin responsiveness is evident in the prostate cancer cell lines, potentially reflecting a similar heterogeneity in the clinical arena. The central hypothesis to be tested in the studies outline in this proposal is that aggressive (androgen-independent) prostate cancer cells proliferate, at least in part, as the result of an escape from activin-regulated growth inhibition.
In Specific Aim I, we will characterize the regulation of the activin response system (activin subunit, activin receptor and follistatin) in both normal and malignant prostate epithelial cells. Specifically we will utilize adult male rat prostates and the LNCaP cells to define the interactions of gonadal steroids, gonadal peptides and activin responsibleness. In parallel, we will also use the PC-3 cells to define the mechanism of activin resistance. In these experiments, we will examine pre-receptor, receptor and post-receptor events that could impart resistance to activin. In so doing, we will test strategies that could be applied to clinical use in preventing cancer cell proliferation. For example, we propose to identify RNA molecules (known as aptamers) by the process of SELEX which could serve to inactivate follistatin and increase activin action. The second specific aim will utilize the Dunning transplant able rat prostate cancer cell lines as a model in which to test these potential therapeutic approaches. In these experiments, we will identify activin responsive and activin resistant Dunning cell lines. We will then examine whether the pharmacologic agents identified in Aim I that increase activin action can improve the clinical performance of animal bearing tumors from the Dunning cancer cell lines.
