title: Activation of the insulin-like growth factor-1 receptor alters p27 regulation by the epidermal growth factor receptor in oral squamous carcinoma cells.
abstract: BACKGROUND
  Although oral squamous cell carcinomas (OSCCs) commonly overexpress the epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors (TKIs) exhibit poor efficacy clinically. Activation of the insulin-like growth factor-1 receptor (IGF1R) induces resistance of OSCC cells to EGFR-TKIs in vitro. This study seeks to evaluate the changes in cell cycle status in OSCC cells in response to gefitinib and IGF1R activation.
  
  
  METHODS
  SCC-25 OSCC cells were used for in vitro analyses.
  
  
  RESULTS
  Gefitinib caused a 50% reduction in S-phase population, and IGF1R activation caused a 2.8-fold increase; combined treatment yielded a baseline S-phase population. Gefitinib treatment increased the cyclin-dependent kinase inhibitor p27, and this was not abrogated by IGF1R activation. pT157-p27 was noted by immunoblot to be decreased on gefitinib treatment, but this was reversed with IGF1R activation. T157 phosphorylation contributes to cytoplasmic localization of p27 where it can promote cell proliferation and cell motility. Using both subcellular fractionation and immunofluorescence microscopy techniques, IGF1R stimulation was noted to increase the relative cytoplasmic localization of p27; this persisted when combined with gefitinib.
  
  
  CONCLUSIONS
  IGF1R activation partially reverses the cell cycle arrest caused by gefitinib in OSCC cells. While IGF1R stimulation does not eliminate the gefitinib-induced increase in total p27, its phosphorylation state and subcellular localization are altered. This may contribute to the ability of the IGF1R to rescue OSCC cells from EGFR-TKI treatment and may have important implications for the use of p27 as a biomarker of cell cycle arrest and response to therapy.
authors.affiliation: Division of Head and Neck Surgical Oncology, Department of Otolaryngology - Head and Neck Surgery, University of Virginia Health System, Charlottesville, VA 22908-0713, USA. mark.jameson@virginia.edu
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Jameson
authors.forename: Linnea E
authors.initials: LE
authors.lastname: Taniguchi
authors.forename: Kyle K
authors.initials: KK
authors.lastname: VanKoevering
authors.forename: Menachem M
authors.initials: MM
authors.lastname: Stuart
authors.forename: Christian R
authors.initials: CR
authors.lastname: Francom
authors.forename: Rolando E
authors.initials: RE
authors.lastname: Mendez
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Beckler
authors.forename: Hans T
authors.initials: HT
authors.lastname: Carlson
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Thomas
authors.forename: Ashraf A
authors.initials: AA
authors.lastname: Khalil
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000648:ultrastructure; D056741:Cyclin D / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000187:drug effects / Q000502:physiology*; D003593:Cytoplasm / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D000077156:Gefitinib; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009062:Mouth Neoplasms / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000502:physiology*; D016196:S Phase / Q000187:drug effects; D013347:Subcellular Fractions / Q000648:ultrastructure
chemical_list: C107875:6-(methylamino)pyrido(3,4-d)pyrimidine; D056741:Cyclin D; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; C058957:insulin-like growth factor 1, des-(1-3)-; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D051058:Oncogene Protein v-akt; D000077156:Gefitinib