Abstract
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.
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This work was supported by NIH grant CA-55823
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McGuire, T., Sebti, S. Geranylgeraniol potentiates lovastatin inhibition of oncogenic H-Ras processing and signaling while preventing cytotoxicity. Oncogene 14, 305–312 (1997). https://doi.org/10.1038/sj.onc.1200819
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DOI: https://doi.org/10.1038/sj.onc.1200819
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