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

// Sofia N. Santos 1 , Mara S. Junqueira 2 , Guilherme Francisco 2 , Manuel Vilanova 3, 4, 5 , Ana Magalhaes 3, 6 , Marcelo Dias Baruffi 7 , Roger Chammas 2 , Adrian L. Harris 8 , Celso A. Reis 3, 5, 6, 9 , Emerson S. Bernardes 1 1 Department of Radiopharmacy, Nuclear Energy Research Institute, Radiopharmacy Center, Sao Paulo, Brazil 2 Department of Center for Translational Oncology Cellular, Biology Group, Center for Translational Oncology, Cancer Institute of the State of Sao Paulo-ICESP, Brazil 3 I3S - Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, Portugal 4 IBMC Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal 5 ICBAS-UP – Instituto de Ciencias Biomedicas Abel Salazar, University of Porto, Porto, Portugal 6 Department of Glycobiology in Cancer, IPATIMUP - Institute of Molecular Pathology and Immunology from the University of Porto, Porto, Portugal 7 Department of Clinical, Toxicological and Bromatological Analysis, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Brazil 8 Department of Medical Oncology, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK 9 Department of Pathology and Oncology, Medical Faculty, University of Porto, Portugal Correspondence to: Emerson S. Bernardes, email: ebernardes@ipen.br Keywords: galectin-3, sialyl-Tn, gastric cancer, glycosylation, chemotherapy resistance Received: September 28, 2015      Accepted: October 21, 2016      Published: November 08, 2016 ABSTRACT 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.