| Literature DB >> 23972127 |
Victor L Thijssen1, Roger Lawrence2, Xander M van Wijk3, Sebastiaan A van den Broek4, Margo Dona5,6, Natasha Naidu7, Arie Oosterhof3, Els M van de Westerlo3, Lisanne J Kusters3, Yasmine Khaled3, Tiina A Jokela8, Patrycja Nowak-Sliwinska1,9, Hannie Kremer5,6,10, Sally E Stringer11, Arjan W Griffioen1, Erwin van Wijk5,6, Floris L van Delft4, Toin H van Kuppevelt3.
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 ∼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.Entities:
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Year: 2013 PMID： 23972127 PMCID： PMC3821560 DOI： 10.1021/cb4004332
Source DB: PubMed Journal: ACS Chem Biol ISSN： 1554-8929 Impact factor: 5.100