The Survivin-mediated radioresistant phenotype of glioblastomas is regulated by RhoA and inhibited by the green tea polyphenol (-)-epigallocatechin-3-gallate
The Survivin-mediated radioresistant phenotype of glioblastomas is regulated by RhoA and inhibited by the green tea polyphenol (-)-epigallocatechin-3-gallate
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DOI：
10.1016/j.brainres.2005.10.009
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发表时间：
2006-02-03
期刊：
影响因子：
2.9
通讯作者：
Béliveau, R
中科院分区：
文献类型：
--
作者：
McLaughlin, N;Annabi, B;Béliveau, R
引言：多形性胶质母细胞瘤（GBM）的侵袭性在放射抗性肿瘤细胞中增强。放疗和化疗的组合已被设想为GBM的治疗方法。本研究的目的是确定表没食子儿茶素-3-没食子酸酯（EGCg），一种绿色茶衍生的抗癌分子，是否可以调节GBM对电离辐射（IR）的反应，以及这是否涉及细胞内信号传导的介质和凋亡蛋白的抑制剂。材料和方法：培养U-87人GBM细胞，并用编码Survivin、RhoA或Caveolin-1的cDNA转染。以亚致死单剂量照射模拟和转染的细胞。通过核细胞计数分析细胞增殖。采用荧光半胱天冬酶-3测定法检测细胞凋亡。蛋白质表达的分析通过Western免疫印迹完成。结果：IR（10戈伊）通过非半胱天冬酶依赖性机制使对照U-87细胞增殖降低40%。Survivin的过表达诱导对IR的细胞保护作用，而RhoA的过表达赋予IR的细胞增敏作用。对照组U-87细胞用EGCg预处理后，其增殖率呈剂量依赖性下降。EGCg的生长抑制作用不被过表达的Survivin所拮抗。而经EGCg预处理的Survivin转染细胞对IR敏感，RhoA表达下调. EGCg靶向癌细胞的促存活细胞内通路的潜在治疗作用建议与IR协同作用。结论：GBM的放射抗性可能是通过依赖于Survivin与RhoA的机制介导的。天然抗癌分子如EGCg与放射治疗的组合可以提高IR治疗的疗效。(C)2005 Elsevier B. V.保留所有权利。
Introduction: Glioblastoma multiforme's (GBM) aggressiveness is potentiated in radioresistant tumor cells. The combination of radiotherapy and chemotherapy has been envisioned as a therapeutic approach for GBM. The goal of this study is to determine if epigallocatechin-3-gallate (EGCg), a green tea-derived anti-cancer molecule, can modulate GBMs' response to ionizing radiation (IR) and whether this involves mediators of intracellular signaling and inhibitors of apoptosis proteins. Material and methods: U-87 human GBM cells were cultured and transfected with cDNAs encoding for Survivin, RhoA or Caveolin-1. Mock and transfected cells were irradiated at sublethal single doses. Cell proliferation was analyzed by nuclear cell counting. Apoptosis was detected using a fluorometric caspase-3 assay. Analysis of protein expression was accomplished by Western immunoblotting. Results: IR (10 Gy) reduced control U-87 cell proliferation by 40% through a caspase-independent mechanism. The overexpression of Survivin induced a cytoprotective effect against IR, while the overexpression of RhoA conferred a cytosensitizing effect upon IR. Control U-87 cells pretreated with EGCg exhibited a dose-dependent decrease in their proliferation rate. The growth inhibitory effect of EGCg was not antagonized by overexpressed Survivin. However, Survivin -transfected cells pretreated with EGCg became sensitive to IR, and their RhoA expression was downregulated. A potential therapeutic effect of EGCg targeting the prosurvival intracellular pathways of cancer cells is suggested to act synergistically with IR. Conclusion: The radioresistance of GBM is possibly mediated by a mechanism dependent on Survivin in conjunction with RhoA. The combination of natural anti-cancerous molecules such as EGCg with radiotherapy could improve the efficacy of IR treatments. (C) 2005 Elsevier B.V. All rights reserved.