PSA is an autocrine survival factor in prostate cancer LNCaP cells

793 Serum prostate specific antigen (PSA) levels are elevated in prostate cancer patients and serve as a diagnostic marker for the disease. Prostate cancer is generally responsive to androgen ablation therapy and produces a drop in PSA levels. In time, hormone-refractory disease often develops and PSA levels once again rise. Under normal circumstances PSA is deposited in the lumen of prostatic ducts, whereas PSA secreted from malignant cells gains access to the circulation. The underlying biochemical mechanisms for the aberrant control of PSA secretion in prostate tumors are not well-known. Regulation of peptide secretion by iPLA 2 -β has recently been reported in non-prostatic tissue. In prostate tissue, both iPLA 2 -β and PSA expression are reportedly under androgen regulation. We therefore investigated whether iPLA 2 -β plays a role in PSA secretion in normal prostate epithelial RWPE-1 cells and in LNCaP prostate cancer cells. We observed an increase in iPLA 2 activity in LNCaP cells that corresponded with an increase in expression of the two active isoforms, LH-iPLA 2 and SH-iPLA 2 , as well as a decrease in the inhibitory ankyrin-iPLA 2 isoform. We further demonstrated that treatment with the iPLA 2 -specfic inhibitor, BEL, inhibited PSA secretion from LNCaP cells and subsequently resulted in cell death. While BEL treatment triggered an apoptotic response in LNCaP cells, normal prostate RWPE-1epithelial cells were not vulnerable to BEL-induced cell death. Addition of exogenous PSA to LNCaP cultures suppressed BEL-induced cell death and addition of anti-PSA antibody reversed the survival effect of PSA. These data demonstrate that iPLA 2 plays a role in regulating PSA secretion from cells and the release of PSA provides an autocrine survival function for LNCaP cells. The mechanism by which PSA imparts its survival effect is not currently understood.