Alpha2,6-sialylation of cell-surface N-glycans inhibits glioma formation in vivo.
Human gliomas express very high levels of cell-surface alpha2,3-linked terminal sialic acids on glycoproteins bearing N-linked oligosaccharides, most notably on alpha3beta1 integrin, which is the predominant integrin found in these tumors. Alpha2,6-linked terminal sialic acids, however, are not expressed. Two stable transfectants were made using a tumorigenic human glioma cell line, U-373 MG. Galbeta1,4GlcNAc alpha2,6-sialyltransferase (ST6Gal I) transfectants were made to replace the endogenous alpha2,3-linked sialic acids with alpha2,6-linked sialic acids. And Galbeta1,3(4)GlcNAc alpha2,3-sialyltransferase (ST3Gal III) transfectants were made to increase further the expression of cell-surface, N-glycan, alpha2,3-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 alpha3beta1 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.
Yamamoto
H
H
Chicago Institute for Neurosurgery and Neuroresearch, Chicago, Illinois 60614, USA.
Oviedo
A
A
Sweeley
C
C
Saito
T
T
Moskal
J R
JR
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005109:Extracellular Matrix / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D039201:Integrin alpha3beta1; D016023:Integrins / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D011134:Polysaccharides / Q000096:biosynthesis / Q000378:metabolism*; D051381:Rats; D012794:Sialic Acids / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
D039201:Integrin alpha3beta1; D016023:Integrins; D007527:Isoenzymes; D011134:Polysaccharides; D012794:Sialic Acids; D012799:Sialyltransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase