Atorvastatin augments temozolomide's efficacy in glioblastoma via prenylation-dependent inhibition of Ras signaling
Atorvastatin augments temozolomide's efficacy in glioblastoma via prenylation-dependent inhibition of Ras signaling
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DOI：
10.1016/j.bbrc.2017.05.147
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发表时间：
2017-07-29
影响因子：
3.1
通讯作者：
Li, Jingwen
中科院分区：
文献类型：
--
作者：
Peng, Peng;Wei, Wei;Li, Jingwen
Ras信号转导经常失调，并在胶质母细胞瘤的维持中发挥重要作用。Ras的正常功能在很大程度上取决于适当的翻译后修饰，称为异戊烯化。因此，靶向蛋白质异戊二烯化代表了胶质母细胞瘤的替代治疗策略。在这项研究中，我们证明了阿托伐他汀抑制异戊二烯化对胶质母细胞瘤是有效的。阿托伐他汀单独剂量依赖性地抑制多种胶质母细胞瘤细胞系的生长和存活。其与替莫唑胺的组合显著增强了替莫唑胺在体外培养细胞系统以及体内异种移植成胶质细胞瘤肿瘤模型中的功效。我们进一步表明，这是通过抑制Ras异戊烯化，导致Ras及其下游信号通路，包括Erk，rS6和e1F4E的激活减少来实现的。我们的研究结果表明，抑制Ras活性阿托伐他汀有效地针对MEK和其他信号通路。我们的研究为阿托伐他汀用于胶质母细胞瘤的潜在治疗提供了基本证据。(C)2017爱思唯尔公司All rights reserved.
Ras signaling is often dysregulated and plays essential roles for the maintenance of glioblastoma. The proper function of Ras depends largely on the appropriate post-translational modification termed prenylation. Targeting protein prenylation therefore represents an alternative therapeutic strategy in glioblastoma. In this study, we demonstrate that prenylation inhibition by atorvastatin is active against glioblastoma. Atorvastatin alone dose-dependently inhibits growth and survival of multiple glioblastoma cell lines. Its combination with temozolomide significantly enhances temozolomide's efficacy in in vitro cultured cell system as well as in vivo xenograft glioblastoma tumor model. We further show that this is achieved by the inhibition of Ras prenylation, leading to decreased activation of Ras and its downstream signaling pathways, including Erk, rS6 and e1F4E. Our findings suggest that inhibition of Ras activity by atorvastatin effectively targets the MEK and other signaling pathways. Our study provides a fundamental evidence to repurpose atorvastatin for a potential treatment of glioblastoma. (C) 2017 Elsevier Inc. All rights reserved.