title: Inhibition of lysophosphatidic acid-induced RhoA activation and tumor cell invasion by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors.
abstract: The mevalonate metabolic pathway is necessary for the isoprenylation of a number of small GTPases. We have previously presented that Rho plays a pivotal role in 1-oleoyl-lysophosphatidic acid (LPA)-induced invasion of rat ascites hepatoma MM1 cells. Herein we report the effect of HMG-CoA reductase inhibitors, fluvastatin and lovastatin, on the in vitro invasion of MM1 cells. Fluvastatin and lovastatin inhibited LPA-induced MM1 cell invasion in a dose-dependent manner. Fluvastatin inhibited LPA-induced translocation of RhoA protein from the cytosol to the membrane and RhoA activation which was measured by pull-down assay for GTP-bound RhoA. Fluvastatin also inhibited the translocation of both endogenous and dominant-active RhoA from the cytosol to the membrane, actin stress fiber assembly and in vitro invasion of the cells expressing dominant-active RhoA (Val14-RhoA). These results indicate that HMG-CoA reductase inhibitors have the potential to reduce RhoA activation and cancer cell invasion by targeting the Rho protein isoprenylation.
authors.affiliation: Department of Tumor Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan. kusama-to@mail.mc.pref.osaka.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kusama
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Mukai
authors.forename: Masako
authors.initials: M
authors.lastname: Ayaki
authors.forename: Fumio
authors.initials: F
authors.lastname: Imamura
authors.forename: Masaharu
authors.initials: M
authors.lastname: Tatsuta
authors.forename: Yoshirou
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Inoue
mesh_terms: D000199:Actins / Q000737:chemistry; D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D009154:Mutation; D021381:Protein Transport; D051381:Rats; D013997:Time Factors; D020742:rhoA GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000199:Actins; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008246:Lysophospholipids; D000077340:Fluvastatin; D006160:Guanosine Triphosphate; D008148:Lovastatin; D020742:rhoA GTP-Binding Protein; C032881:lysophosphatidic acid