title: Interfering with UDP-GlcNAc metabolism and heparan sulfate expression using a sugar analogue reduces angiogenesis.
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.
authors: Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Xander M
authors: XM
authors: van Wijk
authors: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Centre, Amsterdam, The Netherlands.
authors: Victor L
authors: VL
authors: Thijssen
authors: Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, San Diego, California.
authors: Roger
authors: R
authors: Lawrence
authors: Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors: Sebastiaan A
authors: SA
authors: van den Broek
authors: 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.
authors: Margo
authors: M
authors: Dona
authors: Glycotechnology Core, University of California San Diego, San Diego, California.
authors: Natasha
authors: N
authors: Naidu
authors: Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Arie
authors: A
authors: Oosterhof
authors: Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Els M
authors: EM
authors: van de Westerlo
authors: Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Lisanne J
authors: LJ
authors: Kusters
authors: Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Yasmine
authors: Y
authors: Khaled
authors: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors: Tiina A
authors: TA
authors: Jokela
authors: 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.
authors: Patrycja
authors: P
authors: Nowak-Sliwinska
authors: 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.
authors: Hannie
authors: H
authors: Kremer
authors: Cardiovascular Research Group, University of Manchester, Manchester, United Kingdom.
authors: Sally E
authors: SE
authors: Stringer
authors: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Centre, Amsterdam, The Netherlands.
authors: Arjan W
authors: AW
authors: Griffioen
authors: 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.
authors: Erwin
authors: E
authors: van Wijk
authors: Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors: Floris L
authors: FL
authors: van Delft
authors: Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Toin H
authors: TH
authors: van Kuppevelt
mesh_terms: D000818:Animals; D002645:Chickens; D015536:Down-Regulation / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D006497:Heparan Sulfate / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D007067:Iduronic Acid / Q000737:chemistry; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D015027:Zebrafish
chemical_list: D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate; D007067:Iduronic Acid; D014537:Uridine Diphosphate N-Acetylglucosamine; D042461:Vascular Endothelial Growth Factor A
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