Interfering with UDP-GlcNAc metabolism and heparan sulfate expression using a sugar analog reduces angiogenesis
- Authors
- van Wijk, X.M., Thijssen, V.L., Lawrence, R., van den Broek, S.A., Dona, M., Naidu, N., Oosterhof, A., van de Westerlo, E.M., Kusters, L.J., Khaled, Y., Jokela, T.A., Nowak-Sliwinska, P., Kremer, H., Stringer, S.E., Griffioen, A.W., van Wijk, E., van Delft, F.L., and van Kuppevelt, T.H.
- ID
- ZDB-PUB-130904-33
- Date
- 2013
- Source
- ACS Chemical Biology 8(10): 2331-8 (Journal)
- Registered Authors
- Dona, Margo
- Keywords
- none
- MeSH Terms
-
- Animals
- Chickens
- Down-Regulation/drug effects
- Embryo, Nonmammalian/drug effects
- Fibroblast Growth Factor 2/genetics
- Gene Expression Regulation/drug effects*
- Heparitin Sulfate/biosynthesis
- Heparitin Sulfate/genetics*
- Heparitin Sulfate/metabolism
- Iduronic Acid/chemistry
- Neovascularization, Pathologic/physiopathology*
- Signal Transduction/drug effects
- Uridine Diphosphate N-Acetylglucosamine/analogs & derivatives*
- Uridine Diphosphate N-Acetylglucosamine/chemistry
- Uridine Diphosphate N-Acetylglucosamine/metabolism
- Uridine Diphosphate N-Acetylglucosamine/pharmacology*
- Vascular Endothelial Growth Factor A/genetics
- Zebrafish
- PubMed
- 23972127 Full text @ ACS Chem. Biol.
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 96% (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.