Abstract
Changes in glycosylation are considered a hallmark of cancer, and one of the key targets of glycosylation modifications is E-cadherin. We and others have previously demonstrated that E-cadherin has a role in the regulation of bisecting GlcNAc N-glycans expression, remaining to be determined the E-cadherin-dependent signaling pathway involved in this N-glycans expression regulation. In this study, we analysed the impact of E-cadherin expression in the activation profile of receptor tyrosine kinases such as insulin receptor (IR) and IGF-I receptor (IGF-IR). We demonstrated that exogenous E-cadherin expression inhibits IR, IGF-IR and ERK 1/2 phosphorylation. Stimulation with insulin and IGF-I in MDA-MD-435 cancer cells overexpressing E-cadherin induces a decrease of bisecting GlcNAc N-glycans that was accompanied with alterations on E-cadherin cellular localization. Concomitantly, IR/IGF-IR signaling activation induced a mesenchymal-like phenotype of cancer cells together with an increased tumor cell invasion capability. Altogether, these results demonstrate an interplay between E-cadherin and IR/IGF-IR signaling as major networking players in the regulation of bisecting N-glycans expression, with important effects in the modulation of epithelial characteristics and tumor cell invasion. Here we provide new insights into the role that Insulin/IGF-I signaling play during cancer progression through glycosylation modifications.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylglucosamine / metabolism*
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Blotting, Western
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Cadherins / metabolism*
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Cell Line, Tumor
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Cytoplasm / metabolism
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Fluorescent Antibody Technique
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Glycosylation
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Humans
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Insulin / metabolism*
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Insulin-Like Growth Factor I / metabolism*
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Neoplasm Invasiveness*
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Phosphorylation
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Polysaccharides / metabolism
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Real-Time Polymerase Chain Reaction
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Signal Transduction*
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beta Catenin / metabolism
Substances
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Cadherins
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Insulin
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Polysaccharides
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beta Catenin
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Insulin-Like Growth Factor I
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Acetylglucosamine
Grants and funding
Financial support from Brazil: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (Student grant – process number: 6155/11-1) and Conselho Nacional de Desenvolvimento Científico e Tecnológico. Financial support from Portugal: SSP acknowledges Fundação para a Ciência e Tecnologia, FCT [SFRH/BPD/63094/2009], the Luso-American Foundation (FLAD), and the bilateral protocol between FCT/ CAPES 2013-2015. IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education, and is partially supported by FCT. This work was supported by grants from the Portuguese Foundation for Science and Technology (FCT), project grants [PTDC/CVT/111358/2009; PIC/IC/82716/2007; PTDC/SAU-GMG/110785/2009)], Post-Doc grant to PO [SFRH / BPD / 89764 / 2012]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.