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首页> 外文期刊>Journal of Cellular Physiology >DNA-PKcs Deficiency Inhibits Glioblastoma Cell-Derived Angiogenesis After Ionizing Radiation
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DNA-PKcs Deficiency Inhibits Glioblastoma Cell-Derived Angiogenesis After Ionizing Radiation

机译：DNA-PKcs缺乏抑制胶质母细胞瘤细胞衍生电离后血管生成辐射

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摘要

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a critical role in non-homologous end-joining repair of DNA double-strand breaks (DSB) induced by ionizing radiation (IR). Little is known, however, regarding the relationship between DNA-PKcs and IR-induced angiogenesis; thus, in this study we aimed to further elucidate this relationship. Our findings revealed that lack of DNA-PKcs expression or activity sensitized glioma cells to radiation due to the defective DNA DSB repairs and inhibition of phosphorylated Akt(Ser473). Moreover, DNA-PKcs deficiency apparently mitigated IR-induced migration, invasion and tube formation of human microvascular endothelial cell (HMEC-1) in conditioned media derived from irradiated DNA-PKcs mutant M059J glioma cells or M059K glioma cells that have inhibited DNA-PKcs kinase activity due to the specific inhibitor NU7026 or siRNA knockdown. Moreover, IR-elevated vascular endothelial growth factor (VEGF) secretion was abrogated by DNA-PKcs suppression. Supplemental VEGF antibody to irradiated-conditioned media was negated enhanced cell motility with a concomitant decrease in phosphorylation of the FAK(Try925) and Src(Try416). Furthermore, DNA-PKcs suppression was markedly abrogated in IR-induced transcription factor hypoxia inducible factor-1 (HIF-1) accumulation, which is related to activation of VEGF transcription. These findings, taken together, demonstrate that depletion of DNA-PKcs in glioblastoma cells at least partly suppressed IR-inflicted migration, invasion, and tube formation of HMEC-1 cells, which may be associated with the reduced HIF-1 level and VEGF secretion. Inhibition of DNA-PKcs may be a promising therapeutic approach to enhance radio-therapeutic efficacy for glioblastoma by hindering its angiogenesis. J. Cell. Physiol. 230: 1094-1103, 2015. (c) 2014 Wiley Periodicals, Inc., A Wiley Company
机译：依赖dna的蛋白激酶催化亚基(DNA-PKcs)发挥了至关重要的作用异源end-joining修复的DNA双链断裂(双边带)电离引起的辐射(IR)。关于DNA-PKcs和之间的关系IR-induced血管生成;旨在进一步阐明这种关系。调查结果显示,缺乏DNA-PKcs表达式或敏感神经胶质瘤细胞的活动辐射由于双边带修理有缺陷的DNA和抑制磷酸化Akt (Ser473)。此外,DNA-PKcs明显不足减轻IR-induced迁移,入侵和管人类微血管内皮细胞的形成(HMEC-1)条件媒体来自辐照DNA-PKcs突变M059J神经胶质瘤细胞或抑制DNA-PKcs M059K神经胶质瘤细胞激酶活性由于特定的抑制剂NU7026或siRNA击倒。血管内皮生长因子(VEGF)分泌被DNA-PKcs抑制废除。补充VEGF抗体irradiated-conditioned媒体否定增强细胞活性与相应减少FAK磷酸化(Try925)和Src (Try416)。在IR-induced明显被废除转录因子缺氧诱导因子- 1(HIF-1)积累,这是相关的VEGF转录的激活。综上所述,证明枯竭至少部分DNA-PKcs在胶质母细胞瘤细胞抑制IR-inflicted迁移、入侵和管形成HMEC-1细胞,这可能是与减少HIF-1和VEGF水平分泌。有前途的治疗方法提高radio-therapeutic胶质母细胞瘤的疗效阻碍它的血管生成。230: 1094 - 1103, 2015。Inc .威利公司

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