期刊
ONCOTARGET
卷 7, 期 50, 页码 83570-83587出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.13192
关键词
galectin-3; sialyl-Tn; gastric cancer; glycosylation; chemotherapy resistance
资金
- Sao Paulo Research Foundation (FAPESP) [2012/06875-6]
- Coordination for the Improvement of Higher Education Personnel (CAPES)
- FCT, the Portuguese Foundation for Science and Technology
- FEDER funds through the Operational Programme for Competitiveness Factors-COMPETE
- National Funds through the FCT [PEst-C/SAU/LA0003/2013, PTDC/BBB-EBI/0786/2012 PTDC/BBBEBI/0567/2014]
- GastricGlycoExplorer [316929]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [CNPq] [467646/2014-7]
- Nucleo de Apoio a Pesquisa em Doencas Inflamatorias [NAPDIN] [11.1.21625.01.0]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [12/06875-6] Funding Source: FAPESP
- Fundação para a Ciência e a Tecnologia [PTDC/BBB-EBI/0786/2012, PEst-C/SAU/LA0003/2013] Funding Source: FCT
- Cancer Research UK [11359, 18974, 16466] Funding Source: researchfish
- Medical Research Council [G0300648] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10163] Funding Source: researchfish
- MRC [G0300648] Funding Source: UKRI
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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