title: Broad phenotypic changes associated with gain of radiation resistance in head and neck squamous cell cancer.
abstract: OBJECTIVE
  The central issue of resistance to radiation remains a significant challenge in the treatment of cancer despite improvements in treatment modality and emergence of new therapies. To facilitate the identification of molecular factors that elicit protection against ionizing radiation, we developed a matched model of radiation resistance for head and neck squamous cell cancer (HNSCC) and characterized its properties using quantitative mass spectrometry and complementary assays.
  
  
  RESULTS
  Functional network analysis of proteomics data identified DNA replication and base excision repair, extracellular matrix-receptor interaction, cell cycle, focal adhesion, and regulation of actin cytoskeleton as significantly up- or downregulated networks in resistant (rSCC-61) HNSCC cells. Upregulated proteins in rSCC-61 included a number of cytokeratins, fatty acid synthase, and antioxidant proteins. In addition, the rSCC-61 cells displayed two unexpected features compared with parental radiation-sensitive SCC-61 cells: (i) rSCC-61 had increased sensitivity to Erlotinib, a small-molecule inhibitor of epidermal growth factor receptor; and (ii) there was evidence of mesenchymal-to-epithelial transition in rSCC-61, confirmed by the expression of protein markers and functional assays (e.g., Vimentin, migration).
  
  
  METHODS
  The matched model of radiation resistance presented here shows that multiple signaling and metabolic pathways converge to produce the rSCC-61 phenotype, and this points to the function of the antioxidant system as a major regulator of resistance to ionizing radiation in rSCC-61, a phenomenon further confirmed by analysis of HNSCC tumor samples.
  
  
  CONCLUSIONS
  The rSCC-61/SCC-61 model provides the opportunity for future investigations of the redox-regulated mechanisms of response to combined radiation and Erlotinib in a preclinical setting.
authors.affiliation: 1 Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine , Winston-Salem, North Carolina.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Bansal
authors.forename: Jade
authors.initials: J
authors.lastname: Mims
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Kuremsky
authors.forename: Amy L
authors.initials: AL
authors.lastname: Olex
authors.forename: Weiling
authors.initials: W
authors.lastname: Zhao
authors.forename: Leimiao
authors.initials: L
authors.lastname: Yin
authors.forename: Revati
authors.initials: R
authors.lastname: Wani
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.forename: Brian
authors.initials: B
authors.lastname: Center
authors.forename: Glen S
authors.initials: GS
authors.lastname: Marrs
authors.forename: Mercedes
authors.initials: M
authors.lastname: Porosnicu
authors.forename: Jacquelyn S
authors.initials: JS
authors.lastname: Fetrow
authors.forename: Allen W
authors.initials: AW
authors.lastname: Tsang
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Furdui
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D006801:Humans; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000528:radiation effects*; D011839:Radiation, Ionizing; D000077195:Squamous Cell Carcinoma of Head and Neck; D014407:Tumor Cells, Cultured
chemical_list: D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors