Transcriptional regulation of the prostate cancer antigen RA1c

295 Prostate cancer will affect one in six men and has treatment options limited to surgery, radiation and/or androgen ablation therapies. RA1c (also known as PSGR) is a putative G-protein coupled receptor and has been shown to be specifically up-regulated in prostate cancer. The goal of this work is to understand the regulation of the RA1c gene in prostate cancer, thereby providing insights into the role of RA1c in cancer and potential therapeutic strategies directed against this target. All androgen independent prostate cancer cell lines possess an IL-6 autocrine loop, and patients with advanced prostate cancer have elevated serum IL-6 levels. Although LNCaP cells express the IL-6 receptor, they do not secrete IL-6 (therefore lack autocrine IL-6 signaling), and the effects of IL-6 on LNCaP cells are a subject of controversy. We find that IL-6 leads to growth arrest and apoptosis in LNCaP cells. Exogenous IL-6 also up-regulates RA1c mRNA, an effect that is blocked by the p38-MAPK inhibitor, SB203580. Interestingly, there is a synergistic increase of RA1c message in LNCaP cells treated with IL-6 and either PD98059 (p44/42 MAPK inhibitor) or Rapamycin (mTOR inhibitor). Both of these treatments as well as inhibition of the pro-growth/pro-survival pathways cause RA1c message to significantly increase. LNCaP cells are dependent on androgens for growth and survival, thus growth in serum-free media or in androgen-depleted media leads to G0-G1 arrest. Under serum-free conditions we have found RA1c mRNA to be significantly upregulated in LNCaP cells. The androgen dihydrotestosterone (DHT) does not up-regulate RA1c but rather suppresses, in a dose-dependent manner, the up-regulation of RA1c induced by serum deprivation or IL-6. Taken together these results suggest that RA1c may be a stress-induced gene that could provide a survival advantage to cancer cells.