title: Galectin-3 knockdown increases gefitinib sensitivity to the inhibition of EGFR endocytosis in gefitinib-insensitive esophageal squamous cancer cells.
abstract: 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.
authors: Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China.
authors: Guanghui
authors: G
authors: Cui
authors: Mingwei
authors: M
authors: Cui
authors: Yuhang
authors: Y
authors: Li
authors: Youguang
authors: Y
authors: Liang
authors: Weihao
authors: W
authors: Li
authors: Haizhou
authors: H
authors: Guo
authors: Song
authors: S
authors: Zhao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D037502:Galectin 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D037502:Galectin 3; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib