Interfering with UDP-GlcNAc metabolism and heparan sulfate expression using a sugar analogue reduces angiogenesis.
ACS Chem Biol
; 8(10): 2331-8, 2013 Oct 18.
Article
em En
| MEDLINE
| ID: mdl-23972127
ABSTRACT
Heparan sulfate (HS), a long linear polysaccharide, is implicated in various steps of tumorigenesis, including angiogenesis. We successfully interfered with HS biosynthesis using a peracetylated 4-deoxy analogue of the HS constituent GlcNAc and studied the compound's metabolic fate and its effect on angiogenesis. The 4-deoxy analogue was activated intracellularly into UDP-4-deoxy-GlcNAc, and HS expression was inhibited up to â¼96% (IC50 = 16 µM). HS chain size was reduced, without detectable incorporation of the 4-deoxy analogue, likely due to reduced levels of UDP-GlcNAc and/or inhibition of glycosyltransferase activity. Comprehensive gene expression analysis revealed reduced expression of genes regulated by HS binding growth factors such as FGF-2 and VEGF. Cellular binding and signaling of these angiogenic factors was inhibited. Microinjection in zebrafish embryos strongly reduced HS biosynthesis, and angiogenesis was inhibited in both zebrafish and chicken model systems. All of these data identify 4-deoxy-GlcNAc as a potent inhibitor of HS synthesis, which hampers pro-angiogenic signaling and neo-vessel formation.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Uridina Difosfato N-Acetilglicosamina
/
Regulação da Expressão Gênica
/
Heparitina Sulfato
/
Neovascularização Patológica
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
ACS Chem Biol
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Holanda