Lovastatin induces apoptosis of k-ras-transformed thyroid cells via inhibition of ras farnesylation and by modulating redox state.

Abstract

Transformation of thyroid cells with either K-ras or H-ras viral oncogenes produces cell types with different phenotype and different response to the inhibition of the prenylation pathway by 3-hydroxy-3-methylglutaryl-CoA reductase or farnesyltransferase inhibitors. These inhibitors induce apoptosis in K-ras-transformed FRTL-5 cells (FRTL-5-K-Ras) whereas cell cycle arrest is induced in H-ras-transformed FRTL-5 (FRTL-5-H-Ras). In FRTL-5-K-Ras cells, the product of K-ras gene is implicated in the scavenging of reactive oxygen species (ROS) through the activation of extracellular-signal-regulated kinase (ERK)1/2 kinases. We observed that lovastatin blocked ras activation through inhibition of farnesylation and induced apoptosis, increasing ROS levels through inhibition of ERK1/2 signaling and Mn-SOD expression. Lovastatin-induced apoptosis was due to intracellular ROS increase since both, the antioxidant compound pyrrolidinedithiocarbamate or the SOD-mimetic compound, antagonized apoptosis. Moreover, both p38 mitogen-activated protein kinase and nuclear factor kappaB pathways, activated as a consequence of high ROS levels, are involved in the apoptotic effect, indicating that cell death induced by lovastatin was dependent on oxidative stress. Lovastatin antitumor efficacy in K-ras-dependent thyroid tumors was further confirmed in vivo, proposing a new therapeutic strategy for those tumor diseases that are sustained by an inappropriate K-ras expression.

• Authors: Chiara Laezza, Laura Fiorentino, Simona Pisanti, Patrizia Gazzerro, Michele Caraglia, Giuseppe Portella, Mario Vitale, Maurizio Bifulco
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 86 Issue 12 Pg. 1341-51 (Dec 2008) ISSN: 0946-2716 [Print] Germany
• PMID: 18779944 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Reactive Oxygen Species
• Lovastatin

Topics

• Animals
• Antineoplastic Agents (metabolism, pharmacology)
• Apoptosis
• Cell Cycle (drug effects)
• Cell Line
• Cell Transformation, Neoplastic
• Female
• Genes, ras
• Lovastatin (metabolism, pharmacology)
• Male
• Mice
• Mice, Nude
• Prenylation
• Rats
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Thyroid Gland (cytology, drug effects, metabolism)