Galectin-8 induces endothelial hyperpermeability through the eNOS pathway involving S-nitrosylation-mediated adherens junction disassembly

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dc.contributor.authorZamorano, Patricia
dc.contributor.authorKoning, Tania
dc.contributor.authorOyanadel, Claudia
dc.contributor.authorMardones, Gonzalo A.
dc.contributor.authorEhrenfeld, Pamela
dc.contributor.authorBoric, Mauricio P.
dc.contributor.authorGonzalez, Alfonso
dc.contributor.authorSoza, Andrea
dc.contributor.authorSanchez, Fabiola A.
dc.date.accessioned2025-01-23T21:12:18Z
dc.date.available2025-01-23T21:12:18Z
dc.date.issued2019
dc.description.abstractThe permeability of endothelial cells is regulated by the stability of the adherens junctions, which is highly sensitive to kinase-mediated phosphorylation and endothelial nitric oxide synthase (eNOS)-mediated S-nitrosylation of its protein components. Solid tumors can produce a variety of factors that stimulate these signaling pathways leading to endothelial cell hyperpermeability. This generates stromal conditions that facilitate tumoral growth and dissemination. Galectin-8 (Gal-8) is overexpressed in several carcinomas and has a variety of cellular effects that can contribute to tumor pathogenicity, including angiogenesis. Here we explored whether Gal-8 has also a role in endothelial permeability. We show that recombinant Gal-8 activates eNOS, induces S-nitrosylation of p120-catenin (p120) and dissociation of adherens junction, leading to hyperpermeability of the human endothelial cell line EAhy926. This pathway involves focal-adhesion kinase (FAK) activation downstream of eNOS as a requirement for eNOS-mediated p120 S-nitrosylation. This suggests a reciprocal, yet little understood, regulation of phosphorylation and S-nitrosylation events acting upon adherens junction permeability. In addition, glutathione S-transferase (GST)-Gal-8 pull-down experiments and function-blocking beta 1-integrin antibodies point to beta 1-integrins as cell surface components involved in Gal-8-induced hyperpermeability. Endogenous Gal-8 secreted from the breast cancer cell line MCF-7 has similar hyperpermeability and signaling effects. Furthermore, the mouse cremaster model system showed that Gal-8 also activates eNOS, induces S-nitrosylation of adherens junction components and is an effective hyperpermeability agent in vivo. These results add endothelial permeability regulation by S-nitrosylation as a new function of Gal-8 that can potentially contribute to the pathogenicity of tumors overexpressing this lectin.
dc.fuente.origenWOS
dc.identifier.doi10.1093/carcin/bgz002
dc.identifier.eissn1460-2180
dc.identifier.issn0143-3334
dc.identifier.urihttps://doi.org/10.1093/carcin/bgz002
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/100951
dc.identifier.wosidWOS:000472792800016
dc.issue.numero2
dc.language.isoen
dc.pagina.final323
dc.pagina.inicio313
dc.revistaCarcinogenesis
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleGalectin-8 induces endothelial hyperpermeability through the eNOS pathway involving S-nitrosylation-mediated adherens junction disassembly
dc.typeartículo
dc.volumen40
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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