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2,6-Sialylation of Cell-Surface N-Glycans Inhibits Glioma Formation in Vivo¹

Chicago Institute for Neurosurgery and Neuroresearch, Chicago, Illinois 60614

Human gliomas express very high levels of cell-surface 2,3-linked terminal sialic acids on glycoproteins bearing N-linked oligosaccharides, most notably on 3ß1 integrin, which is the predominant integrin found in these tumors. 2,6-linked terminal sialic acids, however, are not expressed. Two stable transfectants were made using a tumorigenic human glioma cell line, U-373 MG. Galß1,4GlcNAc 2,6-sialyltransferase (ST6Gal I) transfectants were made to replace the endogenous 2,3-linked sialic acids with 2,6-linked sialic acids. And Galß1,3(4)GlcNAc 2,3-sialyltransferase (ST3Gal III) transfectants were made to increase further the expression of cell-surface, N-glycan, 2,3-linked sialic acids. Although ST3Gal III transfection resulted in increased invasivity when compared with parental U-373 MG and vector-transfected control cells in vitro, ST6Gal I transfection abolished invasion in vitro and induced alterations in both cell morphology, cell-spreading, and adhesion-mediated protein tyrosine phosphorylation. Furthermore, the ST6Gal I transfectants produced no intracranial tumors in severe combined immunodeficient mice, whereas parental U-373 MG cells, the vector-transfected control cells, and ST3Gal III-transfected U-373 MG cells did. These results suggest that both the linkage and expression levels of the terminal sialic acids of 3ß1 integrin N-glycans play an important role in glioma cell-extracellular matrix interactions. Thus, manipulating ST6Gal I gene expression may have therapeutic potential for the treatment of malignant gliomas.

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