Atorvastatin prevents RhoC isoprenylation, invasion, and metastasis in human melanoma cells.
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.
Collisson
Eric A
EA
Department of Medicine, Division of Dermatology, Harbor-UCLA (University of California-Los Angeles), Torrance, CA 90509, USA.
Kleer
Celina
C
Wu
Mei
M
De
Abhijit
A
Gambhir
Sanjiv S
SS
Merajver
Sofia D
SD
Kolodney
Michael S
MS
D000818:Animals; D000069059:Atorvastatin; D002465:Cell Movement; D049452:Green Fluorescent Proteins; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000188:drug therapy; D015151:Immunoblotting; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010957:Plasmids / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011758:Pyrroles / Q000494:pharmacology*; D026362:Serum Response Factor / Q000378:metabolism; D013347:Subcellular Fractions; D013997:Time Factors; D014407:Tumor Cells, Cultured; D018631:ras Proteins; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008164:Luminescent Proteins; D011758:Pyrroles; D026362:Serum Response Factor; D049452:Green Fluorescent Proteins; D000069059:Atorvastatin; D008156:Luciferases; C066690:RHOC protein, human; C512911:Rhoc protein, mouse; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein