Galectin-3 knockdown increases gefitinib sensitivity to the inhibition of EGFR endocytosis in gefitinib-insensitive esophageal squamous cancer cells.

Esophageal cancer (EC) is one of the most aggressive malignancies with a distinctly high incidence and mortality rate. Esophageal squamous cell carcinoma (ESCC) is the major histologic subtype of EC, with 40-70 % of tumors overexpressing the epidermal growth factor receptor (EGFR). Blockade of EGFR signal transduction may be a promising and effective strategy for EC therapy. However, the therapeutic efficacy of EGFR-tyrosine kinase inhibitors is clinically limited because of drug resistance. Galectin-3, a member of the animal lectin family, has been associated with a variety of biological functions and the progression of multiple tumors, including ESCC. In this study, we investigated the role of galectin-3 involved in potential gefitinib-resistance mechanisms in EGFR-positive ESCC cell lines. The results revealed that gefitinib treatment induced different inhibitory effects on cell viability, cell cycle progression and cell invasion in gefitinib-sensitive KYSE-450 and gefitinib-insensitive TE-8 cells with different levels of galectin-3 expression. Interestingly, we further found that EGF-induced EGFR endocytosis and EGFR signaling were different between gefitinib-sensitive and gefitinib-insensitive ESCC cell lines. Galectin-3 inhibition in combination with gefitinib treatment induced greater inhibitory effects on cell viability, cell cycle progression and cell invasion in gefitinib-insensitive TE-8 cells. Moreover, galectin-3 inhibition increased the gefitinib sensitivity of TE-8 cells in terms of EGFR endocytosis in vitro and anti-tumor effects in vivo. Taken together, galectin-3 knockdown increased gefitinib sensitivity through the inhibition of EGFR endocytosis in gefitinib-insensitive ESCC cells and galectin-3 may be a rational therapeutic target in ESCC with gefitinib resistance.