DNA-PKcs Deficiency Inhibits Glioblastoma Cell-Derived Angiogenesis After Ionizing Radiation

• Published in: Journal of cellular physiology 2015-05, Vol.230 (5), p.1094-1103
• Main Authors: Liu, Yang, Zhang, Luwei, Liu, Yuanyuan, Sun, Chao, Zhang, Hong, Miao, Guoying, Di, Cui Xia, Zhou, Xin, Zhou, Rong, Wang, Zhenhua
• Format: Article
• Language: English
• Subjects: Brain Neoplasms - blood supply; Brain Neoplasms - pathology; Brain Neoplasms - radiotherapy; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - radiation effects; Chromones - pharmacology; Culture Media, Conditioned - pharmacology; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded - drug effects; DNA Breaks, Double-Stranded - radiation effects; DNA Repair - drug effects; DNA Repair - radiation effects; DNA-Activated Protein Kinase - antagonists & inhibitors; DNA-Activated Protein Kinase - deficiency; DNA-Activated Protein Kinase - metabolism; Endothelial Cells - drug effects; Endothelial Cells - pathology; Endothelial Cells - radiation effects; Glioblastoma - blood supply; Glioblastoma - pathology; Glioblastoma - radiotherapy; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Ionizing radiation; Morpholines - pharmacology; Neoplasm Invasiveness; Neovascularization, Pathologic - etiology; Neovascularization, Pathologic - prevention & control; Neovascularization, Physiologic - drug effects; Radiation Tolerance - drug effects; Radiation Tolerance - radiation effects; Radiation, Ionizing; RNA, Small Interfering - metabolism; Signal Transduction - drug effects; Signal Transduction - radiation effects; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.24841

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 AktSer473. 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 FAKTry925 and SrcTry416. Furthermore, DNA‐PKcs suppression was markedly abrogated in IR‐induced transcription factor hypoxia inducible factor‐1α (HIF‐1α) 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‐1α 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. © 2014 Wiley Periodicals, Inc., A Wiley Company