title: Simvastatin modulates the adhesion and growth of hepatocellular carcinoma cells via decrease of integrin expression and ROCK.
abstract: Hepatocellular carcinoma (HCC) has become a global health concern and is one of the leading causes of cancer death after lung and gastric cancers. It has been suggested that the 3-hydroxy-3-methyl-glutarylcoenzyme-CoA (HMG-CoA) reductase inhibitor simvastatin exhibits anticancer properties. To this end, we analyzed the influence of simvastatin on the cell growth and adhesion of HCC and evaluated the yet poorly characterized mechanism of action of simvastatin in HCC. HepG2 and Huh7 cells were treated with simvastatin (16-64 μM) for different time periods. Cell proliferation using the MTT assay and tumor cell adhesion to endothelial cell monolayers were evaluated. ß1, ß3 and α2 integrin adhesion receptors and the downstream target of simvastatin Rho-dependent kinase (ROCK) were analyzed by Western blot. Further blocking studies with the ROCK-inhibitor H1152 and anti-integrin ß1 and ß3 antibodies were carried out. Simvastatin treatment inhibited dose-dependently tumor cell growth and attachment to endothelium. The inhibitory effect of simvastatin on cell adhesion was associated with decreased expression of ß1, ß3 and α2 integrins. Furthermore, simvastatin strongly reduced the expression of ROCK-I and activated MYPT, an indicator of ROCK activity. Also, the ROCK-inhibitor H1152 reduced the adhesive capacity of the tumor cells. Anti-adhesive effects of simvastatin were prevented by exogenous mevalonate, a downstream product of HMG-CoA. Tumor cell adhesion to endothelium was significantly impaired following incubation with functional anti-ß1 antibody. Simvastatin modifies the expression of cell adhesion molecules leading to reduced tumor cell growth and invasion. These beneficial effects of simvastatin may be mediated by ROCK. The data presented may point to novel treatment options for HCC.
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Hospitals of the Goethe-University Frankfurt am Main, 60590 Frankfurt, Germany. info@bornarelja.com
authors.forename: Borna
authors.initials: B
authors.lastname: Relja
authors.forename: Frank
authors.initials: F
authors.lastname: Meder
authors.forename: Minhong
authors.initials: M
authors.lastname: Wang
authors.forename: Roman
authors.initials: R
authors.lastname: Blaheta
authors.forename: Dirk
authors.initials: D
authors.lastname: Henrich
authors.forename: Ingo
authors.initials: I
authors.lastname: Marzi
authors.forename: Mark
authors.initials: M
authors.lastname: Lehnert
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D016023:Integrins / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008798:Mevalonic Acid / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000378:metabolism* / Q000502:physiology
chemical_list: C459092:2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016023:Integrins; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019821:Simvastatin; D054460:rho-Associated Kinases; D008798:Mevalonic Acid