Inhibition of lysophosphatidic acid-induced RhoA activation and tumor cell invasion by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors.
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.
Kusama
Toshiyuki
T
Department of Tumor Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan. kusama-to@mail.mc.pref.osaka.jp
Mukai
Mutsuko
M
Ayaki
Masako
M
Imamura
Fumio
F
Tatsuta
Masaharu
M
Matsumoto
Yoshirou
Y
Nakamura
Hiroyuki
H
Inoue
Masahiro
M
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*
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