DNA-PKcs deficiency inhibits glioblastoma cell-derived angiogenesis after ionizing radiation.

Abstract

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-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.

• Authors: Yang Liu, Luwei Zhang, Yuanyuan Liu, Chao Sun, Hong Zhang, Guoying Miao, Cui Xia Di, Xin Zhou, Rong Zhou, Zhenhua Wang
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 230 Issue 5 Pg. 1094-103 (May 2015) ISSN: 1097-4652 [Electronic] United States
• PMID: 25294801 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• 2-(morpholin-4-yl)benzo(h)chromen-4-one
• Chromones
• Culture Media, Conditioned
• Hypoxia-Inducible Factor 1, alpha Subunit
• Morpholines
• RNA, Small Interfering
• Vascular Endothelial Growth Factor A
• DNA-Activated Protein Kinase

Topics

• Brain Neoplasms (blood supply, pathology, radiotherapy)
• Cell Line, Tumor
• Cell Movement (drug effects, radiation effects)
• Chromones (pharmacology)
• Culture Media, Conditioned (pharmacology)
• DNA Breaks, Double-Stranded (drug effects, radiation effects)
• DNA Repair (drug effects, radiation effects)
• DNA-Activated Protein Kinase (antagonists & inhibitors, deficiency, metabolism)
• Endothelial Cells (drug effects, pathology, radiation effects)
• Glioblastoma (blood supply, pathology, radiotherapy)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Morpholines (pharmacology)
• Neoplasm Invasiveness
• Neovascularization, Pathologic (etiology, prevention & control)
• Neovascularization, Physiologic (drug effects)
• RNA, Small Interfering (metabolism)
• Radiation Tolerance (drug effects, radiation effects)
• Radiation, Ionizing
• Signal Transduction (drug effects, radiation effects)
• Vascular Endothelial Growth Factor A (metabolism)