title: Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells.
abstract: The 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, also called statins, are commonly used as lipid-lowering drugs that inhibit cholesterol biosynthesis. An anticancer effect, as a pleiotropic function of certain statins, has been hypothesized. In the present study, we investigated the effect of simvastatin, one of the natural statins, on cell proliferation, cell cycle, invasive activity, and molecular expressions associated with cell-extracellular matrix adhesion, signal transduction, and DNA synthesis in Tu167 and JMAR cells from head and neck squamous cell carcinoma. The addition of simvastatin resulted in a dose-dependent inhibition of cell growth and migration into the extracellular matrix. Considerable morphological changes occurred after treatment with simvastatin, demonstrating loss of cell adhesion and disruption of actin filaments in cytoplasm. The inhibitory effect of simvastatin on cell proliferation seemed to be associated with cell cycle arrest and increased expression of p21, p27, and activated caspase-3. The expression of beta1-integrin, a counter adhesion for the extracellular matrix, phosphorylated FAK, and phosphorylated ERK was decreased by treatment with simvastatin. The proapoptotic effect of simvastatin was inhibited by treatment with mevalonate. cDNA microarray assay demonstrated that molecular changes resulting from treatment with simvastatin included the up-regulation of cell cycle regulators and apoptosis-inducing factors and the down-regulation of integrin-associated molecules and cell proliferation markers. Of down-regulated genes induced by simvastatin treatment, a significant depletion of thymidylate synthase was confirmed using western blot analysis. These results imply that simvastatin has the potential to be effective for the prevention of the growth and metastasis of cancer cells.
authors.affiliation: Department of Otolaryngology, Hirosaki University school of Medicine, Hirosaki, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Takeda
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Maruya
authors.forename: Takashi
authors.initials: T
authors.lastname: Shirasaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Takenori
authors.initials: T
authors.lastname: Takahata
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.forename: Seiji
authors.initials: S
authors.lastname: Kakehata
authors.forename: Soroku
authors.initials: S
authors.lastname: Yagihashi
authors.forename: Hideichi
authors.initials: H
authors.lastname: Shinkawa
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D008798:Mevalonic Acid / Q000008:administration & dosage / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D010766:Phosphorylation; D015398:Signal Transduction; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000924:Anticholesteremic Agents; D019012:Integrin beta1; D019821:Simvastatin; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D053148:Caspase 3; D008798:Mevalonic Acid