Prostate specific membrane antigen (PSMA) expression gives prostate cancer cells a growth advantage in a physiologically relevant folate environment in vitro.
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-gamma-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-gamma-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-gamma-glutamated folate was added to the media. In the presence of penta-gamma-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.
Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania 15232, USA.
Veronica
V
Yao
Dean J
DJ
Bacich
D000954:Antigens, Surface / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D017077:Culture Media, Conditioned; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000235:genetics / Q000503:physiopathology*; D011624:Pteroylpolyglutamic Acids / Q000032:analysis / Q000494:pharmacology* / Q000502:physiology*
C402107:2-(phosphonomethyl)pentanedioic acid; D000954:Antigens, Surface; D017077:Culture Media, Conditioned; D009943:Organophosphorus Compounds; D011624:Pteroylpolyglutamic Acids; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen