PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA) PROMOTES SURVIVAL OF PROSTATE CANCER CELLS BY INDUCING A PARALLEL ACTIVATION OF THE PI3K/AKT-mTOR AND THE RAS-MAPK PATHWAYS IN THE SAME CELL POPULATION.

Prostate specific membrane antigen (PSMA) has recently emerged as one of the most promising biomarkers in diagnosis and treatment of prostate cancer and it is presently a target of immunotherapy trials. Its low expression in normal prostate epithelial cells greatly increases in high-grade prostate cancers, metastasis, as well as in the endothelium of the neo-vasculature of tumors of different histotype. Several peptide growth factors, cytokines and cell adhesion molecules have been implicated in the progression of prostate cancer as well as in the initiation of the signaling events. Previous studies of our laboratory demonstrated that PSMA recruitment with specific antibodies (PSMA cross-linking) at the cell surface of prostate cancer cell (LNCaP cell) elicits a signaling wave activating MAPKs pathway. This observation prompted us to investigate whether PSMA could activate other signaling pathways at the same time in LNCaP cells. By using this cellular system we demonstrate for the first time that the PSMA cross-linking with specific antibodies activates at the same time PI3K/Akt-mTOR and p38, ERK1/2 MAPKs. As a downstream effect of PSMA induced Akt-mTOR pathway activation, we observed a strong phosphorylation of the pro-apoptotic protein BAD. This observation was confirmed in a different clone of Prostate cancer cells that is the bone-metastasis derived PC3, stably transfected and expressing PSMA. The selective inhibition of PI3K, p38 and ERK1/2 MAPKs with specific inhibitors revealed the two pathways cooperate in the regulation of the death/survival balance of LNCaP cells, thus inducing us to investigate whether PSMA cross-linking would affect survival of the LNCaP cells subjected to an apoptotic stimulus. Tests performed showed that PSMA cross-linking rescued LNCaP cells from cell death induced by serum deprivation, indicating that PSMA could have a possible role in survival support. Previous and present results demonstrate that the high expression of PSMA provides prostate cancer cells with useful tools to be used during the progression towards the advanced hormone-independence which characterizes the most aggressive form of prostate cancer.