title: Inhibition of transendothelial migration and invasion of human breast cancer cells by preventing geranylgeranylation of Rho.
abstract: Rho family GTPases are frequently overexpressed in breast cancers, which regulate cancer cell migration and invasion. They require prenylation, a lipid post-translational modification, for full biological functions. We examined the effects of 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (fluvastatin), a selective farnesyltransferase inhibitor (FTI-277) and a selective geranylgeranyltransferase type I inhibitor (GGTI-298) on in vitro invasive capacity of MDA-MB-231 human breast cancer cells into the endothelial cell monolayer in a transendothelial migration assay. Although, at a maximal dose of 5 microM, fluvastatin did not affect the integrity of endothelial cell monolayer, the transendothelial migration of MDA-MB-231 cells was inhibited potently by fluvastatin in a dose-dependent manner. The transendothelial migration of MDA-MB-231 cells was also inhibited potently by GGTI-298 in a dose-dependent manner but weakly by FTI-277. The inhibitory effects of fluvastatin, GGTI-298 and FTI-277 on MDA-MB-231 cell invasion were shown to correlate well with inhibition of the membrane localization of RhoA and RhoC, but not with Ras. These results suggest that geranylgeranylation step of RhoA and RhoC could be a good therapeutic target for the prevention of invasion and metastasis of breast cancer cells.
authors.affiliation: Department of Tumor Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan. kusama-to@ mc.pref.osaka.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kusama
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Mukai
authors.forename: Masaharu
authors.initials: M
authors.lastname: Tatsuta
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Inoue
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects; D018920:Coculture Techniques; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000502:physiology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007797:Laminin; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D017368:Protein Prenylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011509:Proteoglycans; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein
chemical_list: D001549:Benzamides; D004338:Drug Combinations; C096856:FTI 277; D005229:Fatty Acids, Monounsaturated; C102521:GGTI 298; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; C066737:RHOA protein, human; D000077340:Fluvastatin; D003094:Collagen; D008715:Methionine; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein