Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Geranylgeraniol potentiates lovastatin inhibition of oncogenic H-Ras processing and signaling while preventing cytotoxicity

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Saïd M Sebti.

Additional information

This work was supported by NIH grant CA-55823

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Keywords

  • Ras inhibition
  • lovastatin
  • geranylgeraniol

Further reading

Search

Quick links