辛伐他汀是3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶的抑制剂,它是胆固醇合成途径的限速酶。它已在临床上用作降低低密度脂蛋白(LDL)胆固醇水平的降脂剂。此外,抗肿瘤活性已被证明。虽然辛伐他汀减弱小GTP酶的戊烯化,它对细胞分裂的影响,小GTP酶在其中发挥重要作用,尚未被检查为其细胞抑制作用的潜在机制。在这项研究中,我们确定了它对细胞分裂的影响.细胞周期同步实验表明,在浓度低于IC50的辛伐他汀处理的细胞中,有丝分裂进程会延迟。延时成像分析表明有丝分裂的持续时间,尤其是从有丝分裂进入到后期开始,被延长了。此外,辛伐他汀增加了表现出定向错误的后期/末期和气泡形成的细胞数量。纺锤体组装检查点(SAC)激酶Mpsl的抑制消除了有丝分裂延迟。此外,表现出BubR1(SAC的重要组成部分)的动粒定位的细胞数量,增加了,提示SAC参与有丝分裂延迟。有丝分裂进入时F-肌动蛋白形成和细胞变圆的增强表明皮质肌动蛋白动力学受到辛伐他汀的影响。胆固醇去除剂甲基-β-环糊精(MβCD)加速有丝分裂进程与辛伐他汀不同,这表明质膜的胆固醇丢失与有丝分裂延迟无关。值得注意的是,小GTPaseRhoA,这是皮质肌动蛋白动力学的关键因素,表现出上调的表达。此外,Rap1可能不是香叶基香叶酰化的。我们的结果表明,辛伐他汀通过修饰小的GTP酶影响肌动蛋白动力学,从而激活主轴组装检查点并引起异常细胞分裂。
Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which is a rate-limiting enzyme of the cholesterol synthesis pathway. It has been used clinically as a lipid-lowering agent to reduce low-density lipoprotein (LDL) cholesterol levels. In addition, antitumor activity has been demonstrated. Although simvastatin attenuates the prenylation of small GTPases, its effects on cell division in which small GTPases play an important role, have not been examined as a mechanism underlying its cytostatic effects. In this study, we determined its effect on cell division. Cell cycle synchronization experiments revealed a delay in mitotic progression in simvastatin-treated cells at concentrations lower than the IC50. Time-lapse imaging analysis indicated that the duration of mitosis, especially from mitotic entry to anaphase onset, was prolonged. In addition, simvastatin increased the number of cells exhibiting misoriented anaphase/telophase and bleb formation. Inhibition of the spindle assembly checkpoint (SAC) kinase Mps1 canceled the mitotic delay. Additionally, the number of cells exhibiting kinetochore localization of BubR1, an essential component of SAC, was increased, suggesting an involvement of SAC in the mitotic delay. Enhancement of F-actin formation and cell rounding at mitotic entry indicates that cortical actin dynamics were affected by simvastatin. The cholesterol removal agent methyl-β-cyclodextrin (MβCD) accelerated mitotic progression differently from simvastatin, suggesting that cholesterol loss from the plasma membrane is not involved in the mitotic delay. Of note, the small GTPase RhoA, which is a critical factor for cortical actin dynamics, exhibited upregulated expression. In addition, Rap1 was likely not geranylgeranylated. Our results demonstrate that simvastatin affects actin dynamics by modifying small GTPases, thereby activating the spindle assembly checkpoint and causing abnormal cell division.