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Journal of Lipid Research, Vol. 49, 929-938, May 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Thematic Review

Thematic Review Series: Sphingolipids. Ganglioside GM3 suppresses the proangiogenic effects of vascular endothelial growth factor and ganglioside GD1a^*

Purna Mukherjee, Anthony C. Faber, Laura M. Shelton, Rena C. Baek, Thomas C. Chiles and Thomas N. Seyfried¹

Department of Biology, Boston College, Chestnut Hill, MA 02467

^* This research was supported by National Institutes of Health Grants NS-055195 and CA-102135 and by the Boston College Research Expense Fund.

Published, JLR Papers in Press, February 20, 2008.

¹ To whom correspondence should be addressed. e-mail: thomas.seyfried{at}bc.edu

Gangliosides are sialic acid-containing glycosphingolipids that have long been associated with tumor malignancy and metastasis. Mounting evidence suggests that gangliosides also modulate tumor angiogenesis. Tumor cells shed gangliosides into the microenvironment, which produces both autocrine and paracrine effects on tumor cells and tumor-associated host cells. In this study, we show that the simple monosialoganglioside GM3 counteracts the proangiogenic effects of vascular endothelial growth factor (VEGF) and of the complex disialoganglioside GD1a. GM3 suppressed the action of VEGF and GD1a on the proliferation of human umbilical vein endothelial cells (HUVECs) and inhibited the migration of HUVECs toward VEGF as a chemoattractant. Enrichment of added GM3 in the HUVEC membrane also reduced the phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR-2) and downstream Akt. Moreover, GM3 reduced the proangiogenic effects of GD1a and growth factors in the in vivo Matrigel plug assay. Inhibition of GM3 biosynthesis with the glucosyl transferase inhibitor, N-butyldeoxynojirimycin (NB-DNJ), increased HUVEC proliferation and the phosphorylation of VEGFR-2 and Akt. The effects of NB-DNJ on HUVECs were reversed with the addition of GM3. We conclude that GM3 has antiangiogenic action and may possess therapeutic potential for reducing tumor angiogenesis.

Supplementary key words glycosphingolipid • human umbilical endothelial cell migration • matrigel plug assay • growth factor receptor • phosphorylated Akt

Abbreviations: bFGF, basic fibroblast growth factor; EBM, endothelial basal medium; EGFR, epidermal growth factor receptor; EGM-2, endothelial growth medium; HPTLC, high-performance thin-layer chromatography; HUVEC, human umbilical vein endothelial cell; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NB-DNJ, N-butyldeoxynojirimycin; VEGF, vascular endothelial growth factor; VEGFR-2, vascular endothelial growth factor receptor 2

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