Integrins are a family of heterodimeric cell-surface adhesion receptors composed of α and β subunits [8, 9]. Each integrin binds specific ECM components to aggregates present in the cell membrane. Changes in the structure and/or expression of integrins are frequently associated with malignant transformation and tumor progression [8, 10]. It has been reported that SHP099 supplier in highly metastatic melanomas, the expression of ECM receptors such as α2β1 integrin, α3β1 integrin and α4β1 integrin is generally up-regulated [11, 12]. The mevalonate metabolic pathway is essential for membrane formation and the isoprenylation of a number of small GTPases, which are involved in cell growth and differentiation.

The products of this pathway include farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which modify and direct small GTPases to their site of action [13, 14]. The protein targets for isoprenylation include small G proteins, which require post-translational modification to undergo a series of changes that lead to their attachment to the plasma membranes and make them fully functional. The farnesylated Ras proteins are associated with the mitogenic signal transduction that occurs in response to growth factor stimulation

[15]. The geranylgeranylated proteins of the Rho family include RhoA, Rac1, and Cdc42; these proteins regulate signal transduction from receptors in the membrane in a variety of cellular events related to cell adhesion to the ECM, cell morphology, cell motility, and invasion, thereby selleck chemicals acting as molecular switches in the cell [16]. 3-hydroxy-3-methylglutaryl-coenzyme Selleckchem DAPT A (HMG-CoA) reductase is considered to be the major regulatory enzyme of mevalonate

metabolic pathway. HMG-CoA reductase inhibitors (statins) are reversible inhibitors of the rate-limiting step in cholesterol biosynthesis [17]. Most experimental studies using statins have focused on the effects of drugs on tumor cell growth in BCKDHA vitro and in vivo [18–21]. However, limited information is available on the effects of these agents on tumor cell invasion, adhesion, and metastasis [22–25]. Furthermore, there are no detailed reports on the exact mechanism of the inhibitory effects of statins on invasion, adhesion, and metastasis of tumor cells. Statins are widely used clinically; therefore, if they are found to inhibit tumor metastasis, they could have potential use in the future. In the present study, we have investigated the mechanisms by which statins inhibit tumor cell migration, invasion, adhesion, and metastasis in the mouse melanoma cell line B16BL6. Materials and methods Materials Simvastatin was purchased from Wako (Osaka, Japan), and fluvastatin was purchased from Calbiochem (San Diego, CA, USA). These reagents were dissolved in dimethyl sulfoxide (DMSO) and filtered through 0.45-μm syringe filters (IWAKI GLASS, Japan). The dissolved regents were resuspended in phosphate-buffered saline (PBS; pH 7.