Atorvastatin prevents RhoC isoprenylation, invasion, and metastasis in human melanoma cells

• Published in: Molecular cancer therapeutics Vol. 2; no. 10; pp. 941 - 948
• Main Authors: Collisson, Eric A, Kleer, Celina, Wu, Mei, De, Abhijit, Gambhir, Sanjiv S, Merajver, Sofia D, Kolodney, Michael S
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.10.2003
• Subjects: Animals; Atorvastatin Calcium; Cell Movement; Green Fluorescent Proteins; Heptanoic Acids - pharmacology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hypercholesterolemia - drug therapy; Immunoblotting; Immunohistochemistry; Luciferases - metabolism; Luminescent Proteins - metabolism; Melanoma - pathology; Mice; Mice, SCID; Microscopy, Fluorescence; Neoplasm Invasiveness; Neoplasm Metastasis; Plasmids - metabolism; Protein Processing, Post-Translational; Pyrroles - pharmacology; ras Proteins; rho GTP-Binding Proteins - metabolism; rhoC GTP-Binding Protein; Serum Response Factor - metabolism; Subcellular Fractions; Time Factors; Tumor Cells, Cultured
• ISSN: 1535-7163; 1538-8514

Melanoma is a deadly cancer due to its propensity to metastasize. Pharmacological inhibition of cell motility may benefit patients with cutaneous melanoma by preventing metastasis to internal organs. The Rho GTPases are signaling molecules that drive metastasis by controlling cell motility. We found RhoC to be expressed in clinical melanoma specimens and hypothesized that inhibiting its activation might prevent metastasis. Some Rho proteins, such as RhoC, depend on posttranslational geranylgeranylation for biological activity. We investigated the effect that Atorvastatin, a 3-hydroxy 3-methylglutaryl CoA (HMG-CoA) reductase inhibitor that prevents Rho geranylgeranylation, had on subcellular localization and activity of Rho proteins as well as the metastatic ability of melanoma cells. Atorvastatin inhibited Rho activation and reverted the metastatic phenotype of human melanoma cells in vitro . Moreover, Atorvastatin, at plasma levels comparable to those used to treat of hypercholesterolemia, inhibited in vivo metastasis of melanoma cells overexpressing RhoC. These results support further examination of statins for primary prophylaxis of melanoma metastasis.