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Geranylgeraniol potentiates lovastatin inhibition of oncogenic H-Ras processing and signaling while preventing
1Department of Pharmacology, School of Medicine, University of Pittsburgh, Pennsylvania 15261, USA.
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.
Insights
Lovastatin combined with geranylgeraniol (GGOH) effectively blocks cancer-driving H-Ras signals and reduces toxicity. This combination therapy shows promise for cancer treatment by targeting oncogenic H-Ras signaling pathways.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Oncogenic H-Ras protein requires farnesylation for its transforming activity.
- Lovastatin inhibits farnesylation and geranylgeranylation by depleting farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP).
- Lovastatin's clinical use is limited by severe cytotoxic effects.
Purpose of the Study:
- To investigate a novel approach combining lovastatin with geranylgeraniol (GGOH).
- To potentiate lovastatin's ability to inhibit oncogenic H-Ras signaling.
- To rescue lovastatin-induced toxicity.
Main Methods:
- Co-treatment of cells with lovastatin and geranylgeraniol (GGOH).
- Assessment of oncogenic H-Ras processing and mitogen-activated protein kinase (MAPK) activation.
- Evaluation of geranylgeranyltransferase (GGTase) I and II substrate processing.
- Quantification of lovastatin's cytotoxic effects and cell morphology changes.
Main Results:
- GGOH co-treatment enhanced lovastatin's inhibition of H-Ras processing and MAPK activation.
- GGOH preserved the processing of GGTase I and GGTase II substrates.
- GGOH significantly attenuated lovastatin's cytotoxicity (15-fold reduction) and prevented cell rounding.
- A GGOH metabolite was identified as a dual inhibitor of farnesyltransferase and a substrate for GGTases I and II.
Conclusions:
- Geranylgeraniol (GGOH) potentiates the anti-oncogenic and anti-signaling effects of lovastatin.
- GGOH antagonizes lovastatin's cytotoxicity, offering a potential therapeutic strategy.
- The dual action of a GGOH metabolite explains its opposing effects on signaling and toxicity.