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

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