title: Radioresistant head and neck squamous cell carcinoma cells: intracellular signaling, putative biomarkers for tumor recurrences and possible therapeutic targets.
abstract: OBJECTIVE
  Treatment of local and distant head and neck cancer recurrences after radiotherapy remains an unsolved problem. In order to identify potential targets for use in effective therapy of recurrent tumors, we have investigated protein patterns in radioresistant (FaDu-IRR and SCC25-IRR, "IRR cells") as compared to parental (FaDu and SCC25) head and neck carcinoma cells.
  
  
  METHODS
  Radiation resistant IRR cells were derived from parental cells after repeated exposure to ionizing radiation 10 times every two weeks at a single dose of 10 Gy, resulting in a total dose of 100 Gy. Protein profiling in parental and IRR cells was carried out using two-dimensional differential gel electrophoresis (2D-DIGE) followed by MALDI-TOF/TOF mass spectrometry. Cell viability, cell migration assays and Western blot analysis were used to confirm results obtained using the proteome approach.
  
  
  RESULTS
  Forty-five proteins that were similarly modulated in FaDu-IRR and SCC25-IRR cells compared to parental cells were selected to analyze their common targets. It was found that these either up- or down-regulated proteins are closely related to the enhancement of cell migration which is regulated by Rac1 protein. Further investigations confirmed that Rac1 is up-regulated in IRR cells, and inhibiting its action reduces the migratory abilities of these cells. Additionally, the Rac1 inhibitor exerts cytostatic effects in HNSCC cells, mostly in migratory cells.
  
  
  CONCLUSIONS
  Based on these results, we conclude that radioresistant HNSCC cells possess enhanced metastatic abilities that are regulated by a network of migration-related proteins. Rac1 protein may be considered as a putative biomarker of HNSCC radiation resistance, and as a potential therapeutic target for treating local and distant HNSCC recurrences.
authors.affiliation: Department of Therapeutic Radiology and Oncology, Innsbruck Medical University, Austria.
authors.forename: Sergej
authors.initials: S
authors.lastname: Skvortsov
authors.forename: Connie R
authors.initials: CR
authors.lastname: Jimenez
authors.forename: Jaco C
authors.initials: JC
authors.lastname: Knol
authors.forename: Paul
authors.initials: P
authors.lastname: Eichberger
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schiestl
authors.forename: Paul
authors.initials: P
authors.lastname: Debbage
authors.forename: Ira
authors.initials: I
authors.lastname: Skvortsova
authors.forename: Peter
authors.initials: P
authors.lastname: Lukas
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D002465:Cell Movement / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000473:pathology / Q000532:radiotherapy*; D015513:Oncogene Proteins / Q000235:genetics / Q000528:radiation effects; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D012016:Reference Values; D015398:Signal Transduction / Q000528:radiation effects*; D000077195:Squamous Cell Carcinoma of Head and Neck; D014407:Tumor Cells, Cultured / Q000528:radiation effects
chemical_list: D014408:Biomarkers, Tumor; D015513:Oncogene Proteins