Farnesol and geranylgeraniol: Prevention and reversion of lovastatin-induced effects in NIH3T3 cells
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Mevalonic acid-derived intermediates in the cholesterol biosynthetic pathway have been recognized as being critical to the isoprenylation of a variety of growth-regulating proteins, including those of the RAS superfamily. Treatment of cells with lovastatin, a hydroxymethylglutaryl coenyme A (HMG-CoA) reductase inhibitor, depletes cells of mevalonic acid and thus blocks the isoprenylation of proteins in the RAS superfamily. In NIH3T3 cells pretreated with lovastatin, subsequent addition of farnesol (FOH), but not geranylgeraniol (GGOH), reverses lovastatin’s block of RAS isoprenylation. Neither FOH nor GGOH prevents lovastatin-induced inhibition of RAS isoprenylation when added to cells concurrently with lovastatin. In intact cells, 167 μM FOH and 125 μM GGOH decrease incorporation of [14C]acetate into cholesterol by approximately 50 and 75%, respectively. Results suggest that the radiolabel from either [3H]FOH or [3H]GGOH is incorporated into cholesterol. Co-treatment of cells with lovastatin or mevalonic acid did not significantly alter [3H]FOH or [3H]GGOH incorporation into cholesterol. Lovastatin induces cell rounding; GGOH, but not FOH, both prevents and reverses lovastatin-induced cell rounding. These results provide additional evidence for the existence of a novel “isoprenoid shunt” that differentially utilizes FOH and GGOH as metabolic precursors for isoprenoids that have been depleted by lovastatin treatment.
KeywordsLovastatin NIH3T3 Cell Farnesol Mevalonic Acid Bovine Calf Serum
controlled processes serum replacements-1
hydroxymethylglutaryl coenzyme A
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- 3.Endo, A., Kuroda, M., and Tsujita, Y. (1976) ML-236A, ML-236B, and ML-236C, New Inhibitors of Cholesterogenesis Produced by Penicillium citrinium J. Antibiotics 29, 1346–1348.Google Scholar
- 19.Ciosek, C.P., Magnin, D.R., Harrity, T.W., Logan, J.V., Dickson, J.K., Gordon, E.M., Hamilton, K.A., Jolibois, K.G., Kunselman, L.K., Lawrence, R.M., et al. (1993) Lipophilic 1,1-Bisphosphanates Are Potent Squalene Synthase Inhibitors and Orally Active Cholesterol Lowering Agents in vivo, J. Biol. Chem. 268, 24832–24837.PubMedGoogle Scholar
- 21.Ott, R.L. (1993) An Introduction to Statistical Methods and Data Analysis, 4th edn., Duxbury Press, Belmont, California.Google Scholar
- 22.Hohl, R.J., and Lewis, K. (1995) Differential Effects of Monoterpenes and Lovastatin on RAS Processing, J. Biol. Chem. 29, 17508–17512.Google Scholar
- 24.McGuire, T.F., Qian, Y., Vogt, A., Hamilton, A.D., and Sebti, S.M. (1996) Platelet-Derived Growth Factor Receptor Tyrosine Kinase Phosphorylation Requires Protein Geranylgeranylation but Not Farnesylation, J. Biol. Chem. 44, 27402–27407.Google Scholar
- 33.Leonard, S., Beck, L., and Sinensky, M. (1990) Inhibition of Isoprenoid Biosynthesis and the Post-translational Modification of pro-p21ras, J. Biol. Chem. 9, 5157–5160.Google Scholar