Research Papers:

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

Sofia N. Santos _, Mara S. Junqueira, Guilherme Francisco, Manuel Vilanova, Ana Magalhães, Marcelo Dias Baruffi, Roger Chammas, Adrian L. Harris, Celso A. Reis and Emerson S. Bernardes

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Oncotarget. 2016; 7:83570-83587. https://doi.org/10.18632/oncotarget.13192

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Sofia N. Santos1, Mara S. Junqueira2, Guilherme Francisco2, Manuel Vilanova3,4,5, Ana Magalhães3,6, Marcelo Dias Baruffi7, Roger Chammas2, Adrian L. Harris8, Celso A. Reis3,5,6,9, Emerson S. Bernardes1

1Department of Radiopharmacy, Nuclear Energy Research Institute, Radiopharmacy Center, São Paulo, Brazil

2Department of Center for Translational Oncology Cellular, Biology Group, Center for Translational Oncology, Cancer Institute of the State of Sao Paulo-ICESP, Brazil

3I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal

4IBMC Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal

5ICBAS-UP – Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal

6Department of Glycobiology in Cancer, IPATIMUP - Institute of Molecular Pathology and Immunology from the University of Porto, Porto, Portugal

7Department of Clinical, Toxicological and Bromatological Analysis, Faculdade de Ciências Farmaceuticas de Ribeirão Preto, Universidade de São Paulo, Brazil

8Department of Medical Oncology, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

9Department 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


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.

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