DNA-PKcs Deficiency Inhibits Glioblastoma Cell-Derived Angiogenesis After Ionizing Radiation
DNA-PKcs Deficiency Inhibits Glioblastoma Cell-Derived Angiogenesis After Ionizing Radiation
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DNA-PKcs 缺陷会抑制电离辐射后胶质母细胞瘤细胞衍生的血管生成
DOI：
10.1002/jcp.24841
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发表时间：
2015-05-01
影响因子：
5.6
通讯作者：
Wang, Zhenhua
中科院分区：
文献类型：
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作者：
Liu, Yang;Zhang, Luwei;Wang, Zhenhua
DNA依赖性蛋白激酶催化亚基（DNA-PKcs）在电离辐射（IR）诱导的DNA双链断裂（DSB）的非同源末端连接修复中起重要作用。然而，关于DNA-PKcs和IR诱导的血管生成之间的关系知之甚少，因此，在这项研究中，我们的目的是进一步阐明这种关系。我们的研究结果表明，缺乏DNA-PKcs表达或活性敏感胶质瘤细胞辐射由于缺陷的DNA双链断裂修复和磷酸化Akt（Ser 473）的抑制。此外，DNA-PKcs缺陷明显减轻IR诱导的人微血管内皮细胞（HMEC-1）的迁移，侵袭和管形成的条件培养基来自照射DNA-PKcs突变M059 J胶质瘤细胞或M059 K胶质瘤细胞，由于特异性抑制剂NU 7026或siRNA敲低抑制DNA-PKcs激酶活性。此外，IR升高的血管内皮生长因子（VEGF）分泌被废除的DNA-PKcs抑制。补充VEGF抗体的照射条件培养基被否定增强细胞运动性与FAK（Try 925）和Src（Try 416）的磷酸化的伴随减少。此外，DNA-PKcs抑制在IR诱导的转录因子缺氧诱导因子-1（HIF-1）的积累中被显著废除，这与VEGF转录的激活有关。这些发现，综合在一起，表明在胶质母细胞瘤细胞中的DNA-PKcs的消耗至少部分地抑制IR造成的迁移，侵袭，和管形成的HMEC-1细胞，这可能与减少HIF-1水平和VEGF分泌。抑制DNA-PKcs可能是一种有前途的治疗方法，以提高放射治疗胶质母细胞瘤的疗效，阻碍其血管生成。J.细胞。230：1094-1103，2015。(c)2014 Wiley Periodicals，Inc.威利公司
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