Regulation of Androgen Responses in Prostate Cancer by BAG-1

摘要

Androgen ablation therapy and anti-androgenic drugs represent the principal treatments for metastatic prostate cancer. However, nearly all tumors eventually relapse as hormone-refractory disease. A need therefore exists for better understanding of the mechanisms that allow prostate cancer cells to grow in an androgen - independent manner. This study focuses on BAG-1, a protein that is expressed in prostate cancers and which binds to androgen receptors, increasing their sensitivity to androgenic hormones. BAG-1 is a novel regulator of Hsp70 family molecular chaperones that was originally cloned in our laboratory. The activity of many steroid hormone receptors is known to be regulated by Hsp70 and Hsp90 family proteins. Recently, we have discovered that a previously unrecognized isoform of BAG-1, termed BAG-1L, can form complexes with androgen receptors (AR) and potentiate the actions of AR in prostate cancers, markedly lowering the concentrations of dihydrotestosterone needed for AR-mediated transactivation. In contrast, the shorter BAG-1 protein forms complexes with RAR family retinoid receptors, preventing retinoid-induced transactivation of target genes, abrogating cell growth suppression, and blocking apoptosis. Since BAG-1 and BAG-1L are commonly expressed in prostate cancers, we hypothesize that these proteins contribute to mechanisms of tumor resistance to anti-androgen and retinoid-based therapy. In this proposal, we describe experiments designed to further explore the biological roles and molecular mechanisms by which BAG-1 and BAG-1L regulate responses of prostate cancers to steroid hormones that control the proliferation, differentiation and survival of these malignancies.