Journal
HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK
Volume 33, Issue 10, Pages 1448-1457Publisher
WILEY
DOI: 10.1002/hed.21623
Keywords
MAP kinase pathway; ERK; VEGF; radiation resistance; head and neck cancer
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Funding
- Foundation Tumor Research Head and Neck (Wiesbaden, Germany)
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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. (C) 2010 Wiley Periodicals, Inc. Head Neck 33: 1448-1457, 2011
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