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A more recent version of this article appeared on June 20, 2003 Originally published In Press as doi:10.1074/jbc.M303093200 on April 29, 2003
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Papers In Press, published online ahead of print April 9, 2003
J. Biol. Chem, 10.1074/jbc.M303093200
Submitted on March 26, 2003
Revised on April 9, 2003
Accepted on April 9, 2003

Expression patterns of alpha 2,3 sialyltransferases and alpha 1,3 fucosyltransferases determine the mode of Sialyl Lewis X inhibition by disaccharide decoys

Jillian R. Brown, Mark M. Fuster, and Jeffrey D. Esko

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0687

Corresponding Author: jesko{at}ucsd.edu

A variety of human adenocarcinomas express sialylated, fucosylated Lewis blood group antigens on cell surface and secreted mucins. Binding of these antigens to P-selectin on platelets is thought to facilitate formation of platelet-tumor emboli in the circulation, which in turn allows sequestration of the tumor cells in the microvasculature. Here, we report a pharmacologic approach for blocking these interactions through metabolic inhibition of sialylation. Peracetylated forms of Galbeta 1,4GlcNAcbeta -O-naphthalenemethanol (AcGGn-NM) and GlcNAcbeta 1,3Galbeta -O-naphthalenenmethanol (AcGnG-NM) were taken up by LS180 human colon carcinoma cells, O-deacetylated and utilized as biosynthetic intermediates, resulting in heterogeneous oligosaccharides. The primed oligosaccharides included sialylated, sulfated, and fucosylated products based on mass spectrometry. Assembly of free oligosaccharides on the glycosides decoyed glycosylation of cellular glycoproteins, as assessed by altered binding of lectins and carbohydrate-specific antibodies. Expression of alpha 2,3-sialylated oligosaccharides on the cell surface was diminished specifically, whereas alpha 2,6 sialylation and fucosylation were not. In U937 lymphoma cells, the glycosides decreased fucosylation without affecting sialylation. The differential inhibitory activities correlated inversely with fucosyltransferase and sialyltransferase activity based on enzyme assays and microarray analysis. Regardless of the mechanism, the disaccharides blocked the cells from forming selectin ligands and inhibited adhesion to immobilized selectins, suggesting the glycosides might prove useful for interfering with tumor cell adhesion and metastasis.


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