Blockage of Autophagy in C6 Glioma Cells Enhanced Radiosensitivity Possibly by Attenuating DNA-PK-Dependent DSB Due to Limited Ku Nuclear Translocation and DNA Binding
Blockage of Autophagy in C6 Glioma Cells Enhanced Radiosensitivity Possibly by Attenuating DNA-PK-Dependent DSB Due to Limited Ku Nuclear Translocation and DNA Binding
复制标题
由于 Ku 核易位和 DNA 结合有限，C6 胶质瘤细胞中自噬的阻断可能通过减弱 DNA-PK 依赖性 DSB 来增强放射敏感性
DOI：
10.2174/1566524015666150831141112
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发表时间：
2015-01-01
影响因子：
2.5
通讯作者：
Ren, J.
中科院分区：
文献类型：
--
作者：
Liu, C.;He, W.;Ren, J.
多形性胶质母细胞瘤（GBM）是最致命的脑肿瘤，因其对电离辐射（IR）的抵抗而臭名昭著。最近的证据表明，一种可能的机制，使抵抗IR和保护细胞免受治疗应激是细胞自噬。然而，这种促进生存功能的分子基础仍然难以捉摸。在此，我们报告了红外诱导的自噬加速DNA双链断裂（DSB）修复的分子机制。我们证明IR诱导自噬体的积累，这伴随着自噬相关基因beclin-1、atg5、atg7和atg12的表达升高。在体外和体内实验中，Beclin-1敲低可削弱ir介导的自噬诱导，并显著提高胶质瘤细胞对放射治疗的敏感性。此外，我们的数据首次证明了beclin-1敲低的放射增敏效应可能是由于Ku蛋白的核易位和DNA结合活性的破坏以及随之而来的DSB修复的衰减。我们的发现有助于加深我们对红外诱导自噬的分子机制的理解，并为恶性胶质瘤的放射增敏提供了一种有希望的辅助治疗策略。
Glioblastoma multiforme (GBM) is the most lethal brain tumor and notorious for its resistance to ionizing radiation (IR). Recent evidence suggests that one possible mechanism that enables resistance to IR and protects cells against therapeutic stress is cellular autophagy. The molecular basis for this pro-survival function, however, remains elusive. Herein, we report a molecular mechanism by which IR-induced autophagy accelerates the repair of DNA double-strand breaks (DSB). We demonstrate that IR induces the accumulation of autophagosomes, which is accompanied by elevated expression of autophagy-related genes beclin-1, atg5, atg7, and atg12. Beclin-1 knockdown impaired the induction of IR-mediated autophagy and significantly sensitized glioma cells to radiation therapy in vitro and in vivo. Furthermore, our data is the first to demonstrate that the radiosensitizing effect of beclin-1 knockdown may result from the disruption of nuclear translocation and DNA binding activity of Ku proteins and consequent attenuation of DSB repair. Our findings help advance our understanding of the molecular mechanisms underlying IR-induced autophagy and provide a promising adjunctive therapeutic strategy for the radiosensitization of malignant glioma.