O-glycan sialylation alters galectin-3 subcellular localization and decreases chemotherapy sensitivity in gastric cancer

• Autor(a) principal: Santos, S
• Data de Publicação: 2016
• Outros Autores: Junqueira, M, Francisco, G, Vilanova, M, Magalhães, A, Baruffi, M, Chammas, R, Harris, A, Reis, CA, Bernardes, E
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: https://hdl.handle.net/10216/119047
• topic: Animals; Antigens, Tumor-Associated, Carbohydrate/genetics; Antigens, Tumor-Associated, Carbohydrate/metabolism; Antineoplastic Agents/pharmacology; Cell Line, Tumor; Cell Proliferation; Cisplatin/pharmacology; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Galectin 3/metabolism; Glycosylation; Humans; Mice, Inbred BALB C; Mice, Nude; Protein Processing, Post-Translational; Protein Transport; RNA Interference; Sialyltransferases/genetics; Sialyltransferases/metabolism; Stomach Neoplasms/drug therapy; Stomach Neoplasms/genetics; Stomach Neoplasms/metabolism; Stomach Neoplasms/pathology; Time Factors; Transfection; Tumor Burden

ST6GalNAc-I, the sialyltransferase responsible for sialyl-Tn (sTn) synthesis, has been previously reported to be positively associated with cancer aggressiveness. Here we describe a novel sTn-dependent mechanism for chemotherapeutic resistance. We show that sTn protects cancer cells against chemotherapeutic-induced cell death by decreasing the interaction of cell surface glycan receptors with galectin-3 and increasing its intracellular accumulation. Moreover, exogenously added galectin-3 potentiated the chemotherapeutics-induced cytotoxicity in sTn non-expressing cells, while sTn overexpressing cells were protected. We also found that the expression of sTn was associated with a reduction in galectin-3-binding sites in human gastric samples tumors. ST6GalNAc-I knockdown restored galectin-3-binding sites on the cell surface and chemotherapeutics sensibility. Our results clearly demonstrate that an interruption of O-glycans extension caused by ST6GalNAc-I enzymatic activity leads to tumor cells resistance to chemotherapeutic drugs, highlighting the need for the development of novel strategies to target galectin-3 and/or ST6GalNAc-I.