INHIBITION OF PROTEIN FARNESYLTRANSFERASE - A POSSIBLE MECHANISM OF TUMOR PREVENTION BY DEHYDROEPIANDROSTERONE-SULFATE

Dehydroepiandrosterone sulfate (DHEAS) is the most abundant adrenal st eroid with apparent anticarcinogenic properties. Given our recent obse rvation of the dehydroepiandrosterone-mediated inhibition of protein i soprenylation and the fact that 99% of the circulating dehydroepiandro sterone is sulfated, with less than 1% representing the free steroid, me investigated the effects of DHEAS on post-translational isoprenylat ion of proteins. We here report that exposure of HT-29 SF human coloni c adenocarcinoma cells to DHEAS inhibited the incorporation of [H-3]me valonate into cellular proteins in a dose-dependent manner when endoge nous mevalonate synthesis was blocked by lovastatin. Interestingly, si gnificant inhibition was observed at concentrations of DHEAS which are comparable to peak serum levels of this steroid occurring in the seco nd decade of life. Immunoprecipitation revealed that isoprenylation of p21(ras) was also suppressed in DHEAS-treated HT-29 SF cells. In a ce ll-free system, DHEAS inhibited the farnesylation of a biotinylated de capeptide corresponding to the C-terminus of K-ras by 50% at a concent ration of 100 mu M. This suggests that DHEAS inhibits isoprenylation o f cellular proteins, including p21(ras), at a point in the mevalonate pathway distal to 3-hydroxy-3-methylglutaryl-CoA reductase and that th e DHEAS-mediated suppression of protein farnesylation may largely be d ue to inhibition at the level of protein farnesyltransferase. Thus, th ese findings may provide a plausible explanation for the antitumor act ivity of DHEAS.