Geranylgeraniol potentiates lovastatin inhibition of oncogenic H-Ras processing and signaling while preventing cytotoxicity.
Oncogenic H-Ras requires farnesylation for its transforming activity. Lovastatin inhibits both protein farnesylation and geranylgeranylation by decreasing cellular pools of farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), respectively. Use of lovastatin as a chemotherapeutic agent has been precluded by its significant cytotoxic effects. In this report, we describe a novel approach utilizing a combination of lovastatin and geranylgeraniol (GGOH) to potentiate the ability of lovastatin to block oncogenic H-Ras signaling and concomitantly rescue lovastatin toxicity. GGOH co-treatment with lovastatin enhances inhibition of oncogenic H-Ras processing and constitutive activation of mitogen-activated protein kinase (MAPK), and preserves the processing of geranylgeranyltransferase (GGTase) I and GGTase II protein substrates. Moreover, co-treatment with GGOH significantly (15-fold) attenuates the cytotoxic effects of lovastatin as well as prevents lovastatin-induced cell rounding. These results demonstrate that GGOH potentiates the anti-oncogenic/anti-signaling activity of lovastatin while antagonizing its cytotoxicity. These opposing effects are due to a GGOH metabolite that serves simultaneously as a potent inhibitor for farneslyltransferase as well as a substrate for GGTases I and II.
McGuire
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TF
Department of Pharmacology, School of Medicine, University of Pittsburgh, Pennsylvania 15261, USA.
Sebti
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SM
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004224:Diterpenes / Q000378:metabolism / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D011905:Genes, ras / Q000187:drug effects*; D008148:Lovastatin / Q000494:pharmacology*; D051379:Mice; D011494:Protein Kinases / Q000096:biosynthesis*; D015398:Signal Transduction; D014166:Transferases / Q000378:metabolism
D000970:Antineoplastic Agents; D004224:Diterpenes; D008148:Lovastatin; C017338:geranylgeraniol; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D011494:Protein Kinases