Inhibition of protein isoprenylation and p21ras membrane association by dehydroepiandrosterone in human colonic adenocarcinoma cells in vitro.

Treatment of mice and rats with the adrenal steroid, dehydroepiandrosterone (DHEA), protects against spontaneous and chemically induced tumors. The mechanism of the chemopreventive action of DHEA, however, remains uncertain. DHEA has been reported to inhibit cholesterol biosynthesis. Mevalonic acid constitutes the basic precursor not only for cholesterol but also for a variety of nonsterol isoprenoids involved in cell growth. Certain of these nonsterol isoprenoids are utilized for posttranslational modification of proteins including p21ras. We therefore investigated the effects of DHEA upon protein isoprenylation. Twenty-four-h exposure of HT-29 SF human colonic adenocarcinoma cells to 50 microM DHEA was associated with significant incorporation of products of [3H]mevalonate metabolism into several size classes of cellular proteins. The pattern of incorporation was similar to that obtained after treatment with 25 microM lovastatin, a specific 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor. Very little incorporation of label from [3H]mevalonate was observed in untreated cells. This suggests that [3H]mevalonate gains entrance to isoprenylation sites after treatment with DHEA or lovastatin because of depletion of endogenous mevalonate and subsequent inhibition of protein isoprenylation. Isoprenylation plays a critical role in promoting the association of p21ras with the cell membrane. Posttranslational processing and membrane association of p21ras were both found to be inhibited by DHEA. Thus, it is possible that the inhibition of isoprenylation of p21ras and other cellular proteins by DHEA may contribute to its anti-cancer effects.