title: 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.affiliation: Department of Radiation Medicine, Institute of Modern physics, Chinese Academy of Sciences, Lanzhou, China; Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Luwei
authors.initials: L
authors.lastname: Zhang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Guoying
authors.initials: G
authors.lastname: Miao
authors.forename: Cui Xia
authors.initials: CX
authors.lastname: Di
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wang
mesh_terms: D001932:Brain Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D002867:Chromones / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D005909:Glioblastoma / Q000098:blood supply* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C479235:2-(morpholin-4-yl)benzo(h)chromen-4-one; D002867:Chromones; D017077:Culture Media, Conditioned; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009025:Morpholines; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D051747:DNA-Activated Protein Kinase