Interfering with UDP-GlcNAc metabolism and heparan sulfate expression using a sugar analogue reduces angiogenesis.

Autor:	van Wijk XM; Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands., Thijssen VL; Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Centre, Amsterdam, The Netherlands., Lawrence R; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, San Diego, California., van den Broek SA; Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen, The Netherlands., Dona M; Department of Otorhinolaryngology, Head and Neck Surgery, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.; Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands., Naidu N; Glycotechnology Core, University of California San Diego, San Diego, California., Oosterhof A; Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands., van de Westerlo EM; Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands., Kusters LJ; Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands., Khaled Y; Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands., Jokela TA; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland., Nowak-Sliwinska P; Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Centre, Amsterdam, The Netherlands.; Institute of Bio-Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland., Kremer H; Department of Otorhinolaryngology, Head and Neck Surgery, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.; Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.; Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands., Stringer SE; Cardiovascular Research Group, University of Manchester, Manchester, United Kingdom., Griffioen AW; Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Centre, Amsterdam, The Netherlands., van Wijk E; Department of Otorhinolaryngology, Head and Neck Surgery, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.; Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands., van Delft FL; Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen, The Netherlands., van Kuppevelt TH; Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Jazyk:	angličtina
Zdroj:	ACS chemical biology [ACS Chem Biol] 2013 Oct 18; Vol. 8 (10), pp. 2331-8. Date of Electronic Publication: 2013 Sep 03.
DOI:	10.1021/cb4004332
Abstrakt:	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.
Databáze:	MEDLINE
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