title: Deregulation of cap-dependent mRNA translation increases tumour radiosensitivity through reduction of the hypoxic fraction.
abstract: OBJECTIVE
  Tumour hypoxia is an important limiting factor in the successful treatment of cancer. Adaptation to hypoxia includes inhibition of mTOR, causing scavenging of eukaryotic initiation factor 4E (eIF4E), the rate-limiting factor for cap-dependent translation. The aim of this study was to determine the effect of preventing mTOR-dependent translation inhibition on hypoxic cell survival and tumour sensitivity towards irradiation.
  
  
  METHODS
  The effect of eIF4E-overexpression on cell proliferation, hypoxia-tolerance, and radiation sensitivity was assessed using isogenic, inducible U373 and HCT116 cells.
  
  
  RESULTS
  We found that eIF4E-overexpression significantly enhanced proliferation of cells under normal conditions, but not during hypoxia, caused by increased cell death during hypoxia. Furthermore, eIF4E-overexpression stimulated overall rates of tumour growth, but resulted in selective loss of hypoxic cells in established tumours and increased levels of necrosis. This markedly increased overall tumour sensitivity to irradiation.
  
  
  CONCLUSIONS
  Our results demonstrate that hypoxia induced inhibition of translational control through regulation of eIF4E is an important mediator of hypoxia tolerance and radioresistance of tumours. These data also demonstrate that deregulation of metabolic pathways such as mTOR can influence the proliferation and survival of tumour cells experiencing metabolic stress in opposite ways of nutrient replete cells.
authors.affiliation: Department of Radiation Oncology (Maastro Lab), Maastricht University, The Netherlands. Kasper.Rouschop@maastrichtuniversity.nl
authors.forename: Kasper M A
authors.initials: KM
authors.lastname: Rouschop
authors.forename: Ludwig
authors.initials: L
authors.lastname: Dubois
authors.forename: Marco B E
authors.initials: MB
authors.lastname: Schaaf
authors.forename: Twan
authors.initials: T
authors.lastname: van den Beucken
authors.forename: Natasja
authors.initials: N
authors.lastname: Lieuwes
authors.forename: Tom G H
authors.initials: TG
authors.lastname: Keulers
authors.forename: Kim G M
authors.initials: KG
authors.lastname: Savelkouls
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
authors.forename: Albert J
authors.initials: AJ
authors.lastname: van der Kogel
authors.forename: Marianne
authors.initials: M
authors.lastname: Koritzinsky
authors.forename: Bradly G
authors.initials: BG
authors.lastname: Wouters
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009336:Necrosis; D014176:Protein Biosynthesis; D011836:Radiation Tolerance / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D058570:TOR Serine-Threonine Kinases