Inhibition of protein farnesyltransferase: a possible mechanism of tumor prevention by dehydroepiandrosterone sulfate

Dehydroepiandrosterone sulfate (DHEAS) is the most abundant adrenal steroid with apparent anticarcinogenic properties. Given our recent ohservation of the dehydroepiandrosterone-medlated inhibition of protein isoprenylation and the fact that 99% of the circulating dehydroepiandrosterone is sulfated, with less than 1% representing the free steroid, we investigated the effects of DHEAS on post-translational isoprenylation of proteins. We here report that exposure of HT-29 SF human colonic adenocarcinoma cells to DHEAS inhibited the incorporation of [3H]mevalonate into cellular proteins in a dose-dependent manner when endogenous mevalonate synthesis was blocked by lovastatin. Interestingly, significant inhibition was observed at concentrations of DHEAS which are comparable to peak serum levels of this steroid occurring in the second decade of life. Immunoprecipitation revealed that isoprenylation of p21ras was also suppressed in DHEAS treated HT-29 SF cells. In a cell-free system, DHEAS inhibited the farnesylation of a biotinylated decapeptide corresponding to the C-terminus of K-ras by 50% at a concentration of 100 μM. This suggests that DHEAS inhibits isoprenylation of cellular proteins, including p21ras at a point in the mevalonate pathway distal to 3-hydroxy-3-methylglutaryl-CoA reductase and that the DHEAS mediated suppression of protein farnesylation may largely be due to inhibition at the level of protein farnesyltransferase. Thus, these findings may provide a plausible explanation for the antitumor activity of DHEAS.