title: Activation of mitogen-activated protein kinase extracellular signal-related kinase in head and neck squamous cell carcinomas after irradiation as part of a rescue mechanism.
abstract: BACKGROUND
  Irradiation plays a pivotal role in head and neck squamous cell carcinoma (HNSCC) treatment. However, especially recurrent tumors frequently show increased radioresistance. We analyzed irradiation-stimulated mitogen-activated protein kinase (MAPK) signaling pathways to define cellular rescue mechanisms.
  
  
  METHODS
  Irradiated HNSCC cells were screened for MAPK activation and results were confirmed and refined by functional analyses. Extracellular signal-regulated kinase (ERK) inhibitor U0126 application enabled us to specify postradiogenic cellular responses. Vascular endothelial growth factor (VEGF) levels were analyzed additionally.
  
  
  RESULTS
  We observed a pronounced and time-dependent ERK stimulation. Pathway inhibition resulted in decreased radioresistance. Likewise, we found a decrease of VEGF release after inhibitor treatment. ERK activation was confirmed in xenotransplants showing elevated postradiogenic phospho-ERK (pERK) and VEGF levels.
  
  
  CONCLUSIONS
  Our data give evidence for induction of ERK and successive VEGF release in HNSCC during radiotherapy, which might be partially explained by autoregulated cytoprotection maintained by pERK and potentially VEGF. In conclusion, targeting the ERK-VEGF axis might enhance the efficiency of radiotherapy.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Molecular Tumor Biology Laboratory, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. affolter@hno.klinik.uni-mainz.de
authors.forename: Annette
authors.initials: A
authors.lastname: Affolter
authors.forename: Kai
authors.initials: K
authors.lastname: Fruth
authors.forename: Christoph
authors.initials: C
authors.lastname: Brochhausen
authors.forename: Irene
authors.initials: I
authors.lastname: Schmidtmann
authors.forename: Wolf J
authors.initials: WJ
authors.lastname: Mann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brieger
mesh_terms: D000818:Animals; D002070:Butadienes; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000532:radiotherapy; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism* / Q000528:radiation effects; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000528:radiation effects; D009368:Neoplasm Transplantation; D009570:Nitriles; D011879:Radiotherapy Dosage; D015398:Signal Transduction / Q000528:radiation effects*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D042461:Vascular Endothelial Growth Factor A; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases