Simvastatin inactivates β1‐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 β β β β1-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 apoptosisinducing 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. S imvastatin, one of the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, derived from fungal fermentation, is currently used widely as a safe and effective therapeutic agent in the treatment of hypercholesterolemia, contributing to the reduction in morbidity and mortality of atherosclerosis and coronary artery disease.(1) HMG-CoA reductase inhibitors are also commonly referred to as the statins. In addition to their original role in lowering serum cholesterol levels, statins exert antiproliferative and proapoptotic effects in cancer cells by causing cell cycle arrest at the G1-S phase.(2) An anticancer effect with in vitro simvastatin treatment has been reported in several human malignancies, including multiple myeloma, malignant lymphoma, small cell lung carcinoma, and nasopharyngeal undifferentiated carcinoma.(3-6) However, the efficacy and the molecular mechanism of simvastatin on tumor progression has yet to be clarified.Statins target mevalonate, one of the cholesterol precursors, which is catalyzed by HMG-CoA reductase. Overexpression of mevalonate has been reported to be associated with cell survival and proliferation of cancer cells.(7) Another mechanism that plays a ro...

Anti-cancer potential of MAPK pathway inhibition in paragangliomas – effect of different statins on mouse pheochromocytoma cells

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“…The extent of the anti-cancer effects has been shown to vary depending on model and type of statin used [24][25][26][27][28][29][30]. Thus, we evaluated which of the seven currently available statins may be most effective for PHEO/PGL treatment.…”

Role of Claudin-5 in the Attenuation of Murine Acute Lung Injury by Simvastatin

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Simvastatin reduces tumor cell adhesion to human peritoneal mesothelial cells by decreased expression of VCAM-1 and β1 integrin

“…This is associated with reduced adherence of monocytes and lymphocytes (25). Furthermore, simvastatin prevents the growth and metastasis of squamous cell carcinoma in the head and neck through down-regulation of the β 1 integrin chain (26).…”