Molecular mechanism of the anti-cancer activity of cerivastatin, an inhibitor of HMG-CoA reductase, on aggressive human breast cancer cells
Molecular mechanism of the anti-cancer activity of cerivastatin, an inhibitor of HMG-CoA reductase, on aggressive human breast cancer cells
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DOI：
10.1016/s0898-6568(02)00124-9
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发表时间：
2003-03-01
影响因子：
4.8
通讯作者：
Soria, C
中科院分区：
文献类型：
--
作者：
Denoyelle, C;Albanese, P;Soria, C
他汀类药物目前用于治疗高胆固醇血症。最近，我们证明西立伐他汀也能降低侵袭性乳腺癌细胞MDA-MB-231的增殖和侵袭。在这份报告中，一个分子机制来解释其抗癌作用提出了结合研究西立伐他汀对基因表达（芯片）和信号转导通路的影响。首先，西立伐他汀修饰了13个基因的表达，并在蛋白质水平进行了验证。它们可以直接（u-PA、MMP-9、u-PAR、派-1的减少和抑癌基因Wnt-5a和H-cadherin的增加）或通过刺激抗血管生成基因（血小板反应蛋白-2）间接地促进细胞增殖（细胞周期蛋白D1、PCNA、c-myc的下调和p21（wafl）、p19（INK 4d）整合素β 8的上调）和细胞侵袭。通过体内实验证实了抗血管生成活性。其次，我们证明了其抗癌作用的生化机制主要可以通过抑制RhoA依赖的细胞信号传导来解释。RhoA抑制剂（C3外切酶）或显性负突变体RhoA（N19 RhoA）诱导的效应与西立伐他汀相似，这一事实支持了这一假设。总之，西立伐他汀通过阻止RhoA异戊烯化，抑制（i）RhoA/ROCK途径，导致有缺陷的肌动蛋白应力纤维形成，导致细胞运动所需的牵引力丧失，以及（ii）RhoA/FAK/ AKT信号传导途径，可以解释上述大多数癌症相关基因修饰。因此，抑制RhoA细胞信号传导可能是治疗侵袭性形式的乳腺癌的良好策略。(C)2002年爱思唯尔科技有限公司All rights reserved.
wwStatins are currently used for the treatment of hypercholesterolemia. Recently, we demonstrated that cerivastatin also reduces the proliferation and invasion of aggressive breast cancer cells, MDA-MB-231. In this report, a molecular mechanism to explain its anti-cancer action is proposed by combining the study of cerivastatin effect on both gene expression (microarray) and signal transduction pathways. Firstly, the expression of 13 genes was modified by cerivastatin and confirmed at protein level. They could contribute to the inhibition of both cell proliferation (down-regulation of cyclin D1, PCNA, c-myc and up-regulation p21(wafl), p19(INK4d) integrin beta8) and cell invasion, either directly (decrease in u-PA, MMP-9, u-PAR, PAI-1 and increase in anti-oncogenes Wnt-5a and H-cadherin) or indirectly by stimulating an anti-angiogenic gene (thrombospondin-2). The anti-angiogenic activity was confirmed by in vivo experiments. Secondly, we demonstrated that the biochemical mechanism of its anti-cancer action could be mainly explained by the inhibition of RhoA-dependent cell signalling. This hypothesis was supported by the fact that a RhoA inhibitor (C3 exoenzyme) or a dominant negative mutant RhoA (N19RhoA) induced similar effects to those of cerivastatin. In conclusion, cerivastatin, by preventing RhoA prenylation, inhibits (i) the RhoA/ROCK pathway, leading to defective actin stress fibres formation responsible for the loss of traction forces required for cell motility and (ii) the RhoA/FAK/ AKT signalling pathway that could explain the majority of cancer-related gene modifications described above. Thus, the inhibition of RhoA cell signalling could be a good strategy in therapy of aggressive forms of breast cancer. (C) 2002 Elsevier Science Inc. All rights reserved.