title: Wnt/β-catenin pathway involvement in ionizing radiation-induced invasion of U87 glioblastoma cells.
abstract: BACKGROUND
  Radiotherapy has been reported to promote the invasion of glioblastoma cells; however, the underlying mechanisms remain unclear. Here, we investigated the role of the Wnt/β-catenin pathway in radiation-induced invasion of glioblastoma cells.
  
  
  METHODS
  U87 cells were irradiated with 3 Gy or sham irradiated in the presence or absence of the Wnt/β-catenin pathway inhibitor XAV 939. Cell invasion was determined by an xCELLigence real-time cell analyser and matrigel invasion assays. The intracellular distribution of β-catenin in U87 cells with or without irradiation was examined by immunofluorescence and Western blotting of nuclear fractions. We next investigated the effect of irradiation on Wnt/β-catenin pathway activity using TOP/FOP flash luciferase assays and quantitative polymerase chain reaction analysis of β-catenin target genes. The expression levels and activities of two target genes, matrix metalloproteinase (MMP)-2 and MMP-9, were examined further by Western blotting and zymography.
  
  
  RESULTS
  U87 cell invasiveness was increased significantly by ionizing radiation. Interestingly, ionizing radiation induced nuclear translocation and accumulation of β-catenin. Moreover, we found increased β-catenin/TCF transcriptional activities, followed by up-regulation of downstream genes in the Wnt/β-catenin pathway in irradiated U87 cells. Importantly, inhibition of the Wnt/β-catenin pathway by XAV 939, which promotes degradation of β-catenin, significantly abrogated the pro-invasion effects of irradiation. Mechanistically, XAV 939 suppressed ionizing radiation-triggered up-regulation of MMP-2 and MMP-9, and inhibited the activities of these gelatinases.
  
  
  CONCLUSIONS
  Our data demonstrate a pivotal role of the Wnt/β-catenin pathway in ionizing radiation-induced invasion of glioblastoma cells, and suggest that targeting β-catenin is a promising therapeutic approach to overcoming glioma radioresistance.
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, PR China, dongz@tjh.tjmu.edu.cn.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Dong
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Na
authors.initials: N
authors.lastname: Han
authors.forename: Mengxian
authors.initials: M
authors.lastname: Zhang
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Lyu
mesh_terms: D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000473:pathology / Q000532:radiotherapy*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009381:Neoplasms, Radiation-Induced / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000473:pathology* / Q000528:radiation effects; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C544261:XAV939; D051176:beta Catenin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9