Activation of the insulin-like growth factor-1 receptor alters p27 regulation by the epidermal growth factor receptor in oral squamous carcinoma cells
Article first published online: 26 OCT 2012
© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd
Journal of Oral Pathology & Medicine
Volume 42, Issue 4, pages 332–338, April 2013
How to Cite
J Oral Pathol Med (2013) 42: 332−338
- Issue published online: 1 APR 2013
- Article first published online: 26 OCT 2012
- Manuscript Accepted: 17 SEP 2012
- National Institute of Dental and Craniofacial Research. Grant Number: NIDCR; 5K08DE019477
- UVA Cancer Center
- cell cycle regulation;
- cyclin-dependent kinase inhibitor;
- growth factor;
- oral cavity cancer;
- therapeutic resistance
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.
SCC-25 OSCC cells were used for in vitro analyses.
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.
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.