PSA is an important biomarker for diagnosis of and prognosis assessment in prostate cancer. We have previously demonstrated that calcium-independent PLA2 (iPLA2) controls the secretion of PSA and inhibition of iPLA2 causes apoptosis in LNCaP cells. Addition of the PLA2 product arachidonic acid or its eicosanoid derivatives had no discernable effect on iPLA2-mediated apoptosis in LNCaP cells. However, addition of PSA together with iPLA2 inhibitor restored survival and addition of neutralizing antibody to PSA resulted in apoptosis. Addition of neutralizing antibody alone to LNCaP cells is sufficient to cause activation of caspases, indicative of apoptosis. Based on these data, we hypothesized that PSA plays an autocrine role that affects the survival of prostate cancer cells. Since the PI3K/Akt pathway plays a major role in prostate cancer cell survival, we tested whether PSA could activate the PI3K/Akt. Investigation of PSA signaling by western analysis shows thatPSA causes the activation of Akt through phosphorylation at both Ser-473 and Thr-308 in LNCaP cells in a dose and time-dependent fashion. Phosphorylation of Akt was initiated within 2 hr by PSA at concentrations between 200 and 700 ng/ml and incubation at 3 hr required 25 to 200 ng/ml PSA. Treatment with PI3K inhibitors LY294002 and wortmannin in combination with PSA completed inhibited Akt activation. These data indicate that PSA participates in autocrine signaling that contributes to the regulation of survival of prostate cancer cells. While PSA is one of the best biomarkers for the early detection of any cancer, its effect on patient survival is under question. A role for PSA in cancer progression could explain its minimal impact on patient survival while acting as an early warning signal for the disease.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA