title: High resistance to X-rays and therapeutic carbon ions in glioblastoma cells bearing dysfunctional ATM associates with intrinsic chromosomal instability.
abstract: OBJECTIVE
  To investigate chromosomal instability and radiation response mechanisms in glioblastoma cells.
  
  
  METHODS
  We undertook a comparative analysis of two patient-derived glioblastoma cell lines. Their resistance to low and high linear energy transfer (LET) radiation was assessed using clonogenic survival assay and their intrinsic chromosome instability status using fluorescence in situ hybridization. DNA damage was analyzed by pulsed-field gel electrophoresis and by γ-H2AX foci quantification. Expression of DNA damage response proteins was assessed by immunoblot.
  
  
  RESULTS
  Increased radioresistance to X-rays as well as carbon ions was observed in glioblastoma cells exhibiting high levels of naturally occurring chromosomal instability and impaired Ataxia-telangiectasia mutated (ATM) signaling, as reflected by lack of phosphorylation of ATM, CHK2 and p53 after double-strand breaks induction.
  
  
  CONCLUSIONS
  Our results indicate the existence of highly radioresistant glioblastoma cells, characterized by dysfunctional ATM signaling and high levels of intrinsic chromosomal instability.
authors.affiliation: Heidelberg University Hospital, Department of Radiation Oncology and Radiation Therapy , Heidelberg.
authors.forename: Ivana
authors.initials: I
authors.lastname: Dokic
authors.forename: Andrea
authors.initials: A
authors.lastname: Mairani
authors.forename: Stephan
authors.initials: S
authors.lastname: Brons
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schoell
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.forename: Damir
authors.initials: D
authors.lastname: Krunic
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.forename: Anne
authors.initials: A
authors.lastname: Régnier-Vigouroux
authors.forename: Klaus-Josef
authors.initials: KJ
authors.lastname: Weber
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D043171:Chromosomal Instability / Q000528:radiation effects*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects; D023281:Genomics; D005909:Glioblastoma / Q000473:pathology*; D063193:Heavy Ion Radiotherapy; D006801:Humans; D018499:Linear Energy Transfer; D011836:Radiation Tolerance / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects; D014965:X-Rays
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins
keywords: Glioblastoma cells; genomic instability; low and high LET; radioresistance