Enhanced degradation of epidermal growth factor receptor by metformin
Abstract
Aim Epidermal growth factor receptor (EGFR) is one of the most extensively studied molecular targets for newly developed antitumor drugs. Metformin, a widely used antidiabetic drug for type 2 diabetes, is expected to exhibit antitumor activity. Recently, it was reported that EGFR expression in tumor tissues from patients with type 2 diabetes was reduced in patients taking metformin compared with that in patients not taking metformin. Therefore, we investigated the effect of metformin on the expression of EGFR at the cellular level. Methods Cell lines derived from oral squamous cell carcinoma were used to investigate the effect of metformin on the cell proliferation and cellular content of EGFR. Cell proliferation was assessed by direct cell counting and water-soluble tetrazolium (WST)-based colorimetric assay. Expression level of EGFR messenger ribonucleic acid (mRNA) and protein were analyzed by real-time polymerase chain reaction (PCR) and western blotting, respectively. Results The proliferation of all three cell lines used in this study (Ca9-22, SAS, and HSC-2) was suppressed by metformin. Metformin downregulated the cellular content of EGFR without affecting its mRNA expression. Ligand-induced EGFR internalization was accelerated by metformin. Ligand-induced EGFR degradation was inhibited by the lysosomal and proteasomal inhibitors bafilomycin A1 and MG132, respectively. Conclusion These results suggest that metformin reduces EGFR by modifying the intracellular…
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