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J. Biol. Chem., Vol. 278, Issue 26, 23352-23359, June 27, 2003

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Expression Patterns of 2,3-Sialyltransferases and 1,3-Fucosyltransferases Determine the Mode of Sialyl Lewis X Inhibition by Disaccharide Decoys^*

Jillian R. Brown , Mark M. Fuster , Thomas Whisenant ¶ and Jeffrey D. Esko  ||

From the Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093-0687, the Department of Medicine, Division of Pulmonary Medicine, University of California, San Diego, California 92103-0687, and ^¶The Scripps Research Institute, La Jolla, California 92037

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 Gal1,4GlcNAc-O-naphthalenemethanol and GlcNAc1,3Gal-O-naphthalenemethanol 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 2,3-sialylated oligosaccharides on the cell surface was diminished specifically, whereas 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 that the glycosides might prove useful for interfering with tumor cell adhesion and metastasis.

Received for publication, November 5, 2000 , and in revised form, March 26, 2003.

^* This work was supported by NCI, National Institutes of Health (NIH), Grant CA46462 (to J. D. E.), a Glaxo-Wellcome Pulmonary Fellowship award, and a Research Fellowship from the University of California Tobacco-related Disease Research Program (to M. M. F.). The radiolabeled sugar nucleotides were provided by Bradley Hayes through the Glycotechnology Core of the Glycobiology Research and Training Center (University of California, San Diego) and NIH Grant GM61894 (to A. Varki, University of California, San Diego). The gene microarray analysis was conducted by Gene Microarray Core of The Consortium for Functional Glycomics funded by NIGMS, NIH, Grant GM62116. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0687. Tel.: 858-822-1100; Fax: 858-534-5611; E-mail: jesko{at}ucsd.edu.

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