title: Reactive oxygen species activation of MAPK pathway results in VEGF upregulation as an undesired irradiation response.
abstract: BACKGROUND
  Radioresistance limits the effectiveness of radiotherapy in head and neck squamous cell carcinoma. We previously demonstrated post-radiogenic mitogen-activated protein kinase (MAPK) pathway activation and vascular endothelial growth factor (VEGF) release resulting in reduced tumor cell response. Here, we examined the association of this mechanism with the induction of reactive oxygen species (ROS) under irradiation (IR).
  
  
  METHODS
  Intracellular ROS after IR were measured. We modeled radiation-induced ROS by exposure of two SCC lines to H2 O2 and evaluated the impact of irradiation and ROS on ERK phosphorylation by Western blot, immunohistochemistry, and ELISA.
  
  
  RESULTS
  We found elevated pERK levels after treatment with IR and H2 O2 , which could be distinctly suppressed by U0126. Immunohistochemistry and ELISA revealed increased intracellular VEGF levels after H2 O2 application.
  
  
  CONCLUSIONS
  Our data show that irradiation-induced ROS activate the MAPK pathway and release of VEGF. As VEGF is known to be released after cellular distress resulting in cytoprotection, the described mechanism is potentially of importance for therapy success.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Martynas
authors.initials: M
authors.lastname: Drigotas
authors.forename: Annette
authors.initials: A
authors.lastname: Affolter
authors.forename: Wolf J
authors.initials: WJ
authors.lastname: Mann
authors.forename: Juergen
authors.initials: J
authors.lastname: Brieger
mesh_terms: D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects / Q000528:radiation effects; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology / Q000528:radiation effects; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000528:radiation effects*; D009570:Nitriles / Q000494:pharmacology; D011836:Radiation Tolerance; D017382:Reactive Oxygen Species / Q000032:analysis / Q000494:pharmacology / Q000528:radiation effects*; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000528:radiation effects*
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D017382:Reactive Oxygen Species; C113580:U 0126; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: MAP kinase pathway; head and neck squamous cell carcinoma; irradiation; reactive oxygen species; vascular endothelial growth factor