Prostate specific membrane antigen (PSMA) expression gives prostate cancer cells a growth advantage in a physiologically relevant folate environment in vitro

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Abstract
BACKGROUND Prostate specific membrane antigen (PSMA) expression is correlated with stage and grade of prostate cancer suggesting that it confers a growth advantage. We studied if PSMA folate hydrolase activity provides cells a growth advantage in a low folate (LF) micro-environment by hydrolyzing extracellular poly-γ-glutamated folate to a form that cells can import. METHODS Proliferation of LNCaP and DU-145 cells was assessed in media containing low (LF), physiological (PF), or high (HF) folate with or without penta-γ-glutamated folate and a PSMA specific folate hydrolase inhibitor, 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). RESULTS LNCaP cells, which express PSMA, and DU-145 cells, which do not, displayed decreased proliferation when grown in LF or PF compared to HF media. This reduction in proliferation was eliminated in LNCaP cells when penta-γ-glutamated folate was added to the media. In the presence of penta-γ-glutamated folic acid DU-145 cells displayed increased growth but this was still significantly lower than growth in HF medium. Addition of 2-PMPA attenuated the increased growth seen in LNCaP cells but had no effect on DU-145 cell growth. CONCLUSIONS The folate hydrolase activity of PSMA may provide a growth advantage in LF and PF environments. Prostate