The anti-coagulant warfarin prevents the gamma-carboxylation (gla) of target proteins by interfering with the vitamin K cycle through its inhibition of the vitamin K epoxide reductase (VKOR). Most known gla proteins are found in the blood clotting cascade, but we demonstrate using immunoprecipitation and mass spectrometry that the androgen receptor (AR) can also be gamma-carboxylated. This modification occurs at amino acid 2E and can be prevented by warfarin treatment. This residue has been found to be mutated in partial androgen insensitivity syndrome patients. Warfarin, likely through its ability to control carboxylation, alters AR conformation and inhibits AR transcriptional activity, as does siRNA-mediated knockdown of VKOR, the target of warfarin. We further demonstrate that warfarin treatment reduces AR target gene expression in benign mouse prostate tissue in vivo. Interestingly, retrospective studies have shown that prolonged use of warfarin reduces the incidence of prostate cancer, an effect that is not observed for other cancers. In a small series of patients at our institution, we found that one allele of a functional SNP in VKOR is found at a significantly higher rate in prostate cancer patients than would be expected in the general population. We also found that VKOR is highly expressed in normal human prostate epithelia but is lost in cancerous tissue, a pattern of expression that appears to be unique to prostate cancer. We hypothesize that the lower prostate cancer incidence observed in men taking warfarin is due to the ability of warfarin to reduce AR activity, similar to the effect of 5-alpha reductase inhibitors. Importantly, we show for the first time that a nuclear receptor and transcription factor can be regulated by gamma-carboxylation.
By Ben Yi Tew, Teresa Hong, Sumanta K. Pal, Markus Kalkum & Jeremy Jones