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Inhibition of Protein Isoprenylation and p21^ras Membrane Association by Dehydroepiandrosterone in Human Colonic Adenocarcinoma Cells in Vitro¹

Department of Molecular Pharmacology and Therapeutics and Department of Pediatrics, School of Medicine, East Carolina University, Greenville, North Carolina 27858

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 p21^ras. We therefore investigated the effects of DHEA upon protein isoprenylation. Twenty-four-h exposure of HT-29 SF human colonic adenocarcinoma cells to 50 µM 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 µM 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 p21^ras with the cell membrane. Posttranslational processing and membrane association of p21^ras were both found to be inhibited by DHEA. Thus, it is possible that the inhibition of isoprenylation of p21^ras and other cellular proteins by DHEA may contribute to its anti-cancer effects.

¹ This work was supported in part by the Medical Foundation of East Carolina University and by Grant 111 from the Institute of Nutrition of the University of North Carolina at Chapel Hill, S. S. is the recipient of a Technology Transfer Trainee Fellowship from the Biomedical Science Exchange Program between the United States and Germany.

² To whom requests for reprints should be addressed, at the Department of Molecular Pharmacology and Therapeutics, School of Medicine, East Carolina University, Greenville, NC 27858.

Received 7/ 1/91. Accepted 10/ 3/91.

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