Expression patterns of alpha 2,3-sialyltransferases and alpha 1,3-fucosyltransferases determine the mode of sialyl Lewis X inhibition by disaccharide decoys.
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 Galbeta1,4GlcNAcbeta-O-naphthalenemethanol and GlcNAcbeta1,3Galbeta-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 alpha2,3-sialylated oligosaccharides on the cell surface was diminished specifically, whereas alpha2,6-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.
Brown
Jillian R
JR
Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093-0687, USA.
Fuster
Mark M
MM
Whisenant
Thomas
T
Esko
Jeffrey D
JD
D000970:Antineoplastic Agents / Q000494:pharmacology; D001792:Blood Platelets / Q000737:chemistry; D002448:Cell Adhesion / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004187:Disaccharides / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005647:Fucosyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009360:Neoplastic Cells, Circulating / Q000187:drug effects; D009844:Oligosaccharides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000494:pharmacology; D012334:RNA, Neoplasm / Q000032:analysis; D019087:Selectins / Q000378:metabolism; D000080506:Sialyl Lewis X Antigen; D012799:Sialyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
D000970:Antineoplastic Agents; D004187:Disaccharides; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D009844:Oligosaccharides; D012334:RNA, Neoplasm; D019087:Selectins; D000080506:Sialyl Lewis X Antigen; D005647:Fucosyltransferases; C031692:galactoside 3-fucosyltransferase; D012799:Sialyltransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase; C000722087:ST3GAL1 protein, human