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Activation of the insulin‐like growth factor‐1 receptor alters p27 regulation by the epidermal growth factor receptor in oral squamous carcinoma cells
Author(s) -
Jameson Mark J.,
Taniguchi Linnea E.,
VanKoevering Kyle K.,
Stuart Menachem M.,
Francom Christian R.,
Mendez Rolando E.,
Beckler Andrew D.,
Carlson Hans T.,
Thomas Christopher Y.,
Khalil Ashraf A.
Publication year - 2013
Publication title -
journal of oral pathology and medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.887
H-Index - 83
eISSN - 1600-0714
pISSN - 0904-2512
DOI - 10.1111/jop.12014
Subject(s) - gefitinib , epidermal growth factor receptor , insulin like growth factor , cancer research , tyrosine kinase , epidermal growth factor , population , biology , growth factor receptor , growth factor , cell cycle , cell growth , medicine , endocrinology , receptor , signal transduction , microbiology and biotechnology , cancer , biochemistry , environmental health
Background Although oral squamous cell carcinomas ( OSCC s) commonly overexpress the epidermal growth factor receptor ( EGFR ), EGFR tyrosine kinase inhibitors ( TKI s) exhibit poor efficacy clinically. Activation of the insulin‐like growth factor‐1 receptor (IGF1R) induces resistance of OSCC cells to EGFR ‐ TKI s in vitro . This study seeks to evaluate the changes in cell cycle status in OSCC cells in response to gefitinib and IGF 1 R activation. Methods SCC ‐25 OSCC cells were used for in vitro analyses. Results Gefitinib caused a 50% reduction in S ‐phase population, and IGF 1 R 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 IGF 1 R activation. pT 157‐p27 was noted by immunoblot to be decreased on gefitinib treatment, but this was reversed with IGF 1 R 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, IGF 1 R stimulation was noted to increase the relative cytoplasmic localization of p27; this persisted when combined with gefitinib. Conclusions IGF 1 R activation partially reverses the cell cycle arrest caused by gefitinib in OSCC cells. While IGF 1 R 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 IGF 1R 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.