title: 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.
abstract: 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 autophagyrelated 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.
authors: C
authors: C
authors: Liu
authors: W
authors: W
authors: He
authors: M
authors: M
authors: Jin
authors: H
authors: H
authors: Li
authors: H
authors: H
authors: Xu
authors: H
authors: H
authors: Liu
authors: K
authors: K
authors: Yang
authors: T
authors: T
authors: Zhang
authors: G
authors: G
authors: Wu
authors: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 156 Wujiadun Road, Wuhan 430022, P.R. China. jhrenmed@126.com.
authors: J
authors: J
authors: Ren
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000473:pathology* / Q000532:radiotherapy; D000072200:Ku Autoantigen; D009368:Neoplasm Transplantation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance; D051381:Rats; D015854:Up-Regulation
chemical_list: D034961:Antigens, Nuclear; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C512829:Becn1 protein, rat; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D051747:DNA-Activated Protein Kinase; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen