O-glycan sialylation alters galectin-3 subcellular localization and decreases chemotherapy sensitivity in gastric cancer.
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.
Department of Radiopharmacy, Nuclear Energy Research Institute, Radiopharmacy Center, São Paulo, Brazil.
Sofia N
SN
Santos
Department of Center for Translational Oncology Cellular, Biology Group, Center for Translational Oncology, Cancer Institute of the State of Sao Paulo-ICESP, Brazil.
Mara S
MS
Junqueira
Department of Center for Translational Oncology Cellular, Biology Group, Center for Translational Oncology, Cancer Institute of the State of Sao Paulo-ICESP, Brazil.
Guilherme
G
Francisco
I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.|IBMC Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal.|ICBAS-UP - Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.
Manuel
M
Vilanova
I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.|Department of Glycobiology in Cancer, IPATIMUP - Institute of Molecular Pathology and Immunology from the University of Porto, Porto, Portugal.
Ana
A
Magalhães
Department of Clinical, Toxicological and Bromatological Analysis, Faculdade de Ciências Farmaceuticas de Ribeirão Preto, Universidade de São Paulo, Brazil.
Marcelo
M
Dias Baruffi
Department of Center for Translational Oncology Cellular, Biology Group, Center for Translational Oncology, Cancer Institute of the State of Sao Paulo-ICESP, Brazil.
Roger
R
Chammas
Department of Medical Oncology, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Adrian L
AL
Harris
I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.|ICBAS-UP - Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.|Department of Glycobiology in Cancer, IPATIMUP - Institute of Molecular Pathology and Immunology from the University of Porto, Porto, Portugal.|Department of Pathology and Oncology, Medical Faculty, University of Porto, Portugal.
Celso A
CA
Reis
Department of Radiopharmacy, Nuclear Energy Research Institute, Radiopharmacy Center, São Paulo, Brazil.
Emerson S
ES
Bernardes
D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001798:Blood Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D037502:Galectin 3 / Q000378:metabolism*; D037161:Galectins; D006031:Glycosylation; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D034622:RNA Interference; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
D015295:Antigens, Tumor-Associated, Carbohydrate; D000970:Antineoplastic Agents; D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; C428445:LGALS3 protein, human; C055491:sialosyl-Tn antigen; D012799:Sialyltransferases; C038525:CMP-N-acetylneuraminate-alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase; D002945:Cisplatin
chemotherapy resistance; galectin-3; gastric cancer; glycosylation; sialyl-Tn