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

Dehydroepiandrosterone sulfate (DHEAS) is the most abundantadrenal steroid with apparent anticarcinogenic properties. Givenour recent ohservation of the dehydroepiandrosterone-medlatedinhibition of protein isoprenylation and the fact that 99% ofthe circulating dehydroepiandrosterone is sulfated, with lessthan 1% representing the free steroid, we investigated the effectsof DHEAS on post-translational isoprenylation of proteins. Wehere report that exposure of HT-29 SF human colonic adenocarcinomacells to DHEAS inhibited the incorporation of [³H]mevalonateinto cellular proteins in a dose-dependent manner when endogenousmevalonate synthesis was blocked by lovastatin. Interestingly,significant inhibition was observed at concentrations of DHEASwhich are comparable to peak serum levels of this steroid occurringin the second decade of life. Immunoprecipitation revealed thatisoprenylation of p21^ras was also suppressed in DHEAS treatedHT-29 SF cells. In a cell-free system, DHEAS inhibited the farnesylationof a biotinylated decapeptide corresponding to the C-terminusof K-ras by 50% at a concentration of 100 µM. This suggeststhat DHEAS inhibits isoprenylation of cellular proteins, includingp21^ras at a point in the mevalonate pathway distal to 3-hydroxy-3-methylglutaryl-CoAreductase and that the DHEAS mediated suppression of proteinfarnesylation may largely be due to inhibition at the levelof protein farnesyltransferase. Thus, these findings may providea plausible explanation for the antitumor activity of DHEAS.