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1 Department of Medicine, Division of Dermatology, Harbor-UCLA (University of California-Los Angeles),Torrance, CA; 2 Department of Medicine, Division of Dermatology; 3 Crump Institute for Molecular Imaging; 4 Department of Molecular and Medical Pharmacology; 5 Department of Biomathematics; 6 Division of Dermatology, Martin Luther King Jr./Charles R. Drew Medical Center, UCLA School of Medicine, Los Angeles, CA; and 7 Breast and Ovarian Cancer Risk Evaluation Program, Department of Medicine, University of Michigan, Ann Arbor, MI
Requests for Reprints:Michael S. Kolodney, Department of Medicine, Division of Dermatology, Harbor-UCLA, Torrance, CA 90509. E-mail: mkolodney{at}rei.edu
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.
Grant support:James Whittenberg Memorial Research Award and the Don Aronow Memorial Research Award from the Melanoma Research Foundation, an Atorvastatin Research Award from the Pfizer Corporation, and a grant from the Los Angeles Dermatology foundation to M.S.K., NIH grants R0-1 CA82214, SAIRP R24 CA92865, and D.O.E. Contract DE-FC03-87ER60615 to S.S.G., DAMD17-00-1-0345 and NIH-R0-1 CA 77612 to S.D.M. E.A.C. is a postdoctoral trainee supported by USHHS Institutional National Research Service Award T32 CA09056.
Received 4/ 8/03; revised 6/ 5/03; accepted 6/27/03.
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