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Effect of EGFR/IGFR-1β heterodimerization on anti-proliferative activity of gefitinib against colon carcinoma cells
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Abstract:
Objective:To observe the interaction of EGFR with IGFR-1β and to investigate the effect of EGFR inhibitor IGFR-1β on the anti-proliferative activity of gefitinib against colon carcinoma cells. Methods: Interactions between EGFR and IGFR-1β and their association with their downstream signal proteins AKT and MAPK were examined by immunoprecipitation and Western blotting analysis. MTT assay was used to measure cell proliferation of colon carcinoma cells after treatment with IGFR-1 tyrosine kinase inhibitor AG1024, gefitinib or both. Results: Irrespective of gefitinib treatment, EGFR immunoprecipitates from LoVo cells (the gefitinib-sensitive cell line) failed to display IGFR-1β band, whereas HCT116 cells (the gefitinib-resistant cell line) displayed the band and the band became more obvious after treatment with gefitinib. And IGFR-1β band was seen in gefitinib-treated HT29 cells (the gefitinib-moderate-sensitive cell line) but not in non-treated ones. Decreases in Akt and MAPK binding were found in LoVo cells treated with gefitinib, in HT29 cells treated with gefitinib plus AG1024, and in HCT116 cells treated with AG1024 (P<0.05). Gefitinib alone significantly decreased the proliferation rate of LoVo cells compared with control group (P<0.05), and AG1024 alone did not decrease the proliferation rate of LoVo cells; furthermore, gefitinib combined with AG1024 failed to further decrease the proliferation rate of LoVo cells compared with gefitinib group; AG1024 or gefitinib treatment alone did not decrease the proliferation rate of HT29 cells, but combined treatment led to a significant decrease (P<0.05); and AG1024 but not gefitinib alone significantly reduced the proliferation rate of HCT116 cells (P<0.05), whereas combined treatment did not result in a synergistic effect compared with AG1024 group. Conclusion: Resistance of colon carcinoma cells to gefitinib might partly arise from activation of IGFR-1β signaling pathway through the formation of EGFR/IGFR-1β heterodimerization, and administration of AG1024 blocking IGFR-1β activation might increase the sensitivity of colon carcinoma cells to gefitinib.
Keywords:
colon carcinoma cell ; gefitinib ; AG1024 ; epidermal growth factor receptor (EGFR) ; insulin-like growth factor receptor-1(IGFR-1) ; anti-proliferative activity
Project Supported:
Project supported by the Wujieping Medical Foundation (No. EGFR07-07), and the Scientific Foundation of Third Military Medical University
