Overexpression of ST6GalNAcV, a ganglioside-specific α2,6-sialyltransferase, inhibits glioma growth in vivo

Abstract

Aberrant cell-surface glycosylation patterns are present on virtually all tumors and have been linked to tumor progression, metastasis, and invasivity. We have shown that expressing a normally quiescent, glycoprotein-specific α2,6-sialyltransferase (ST6Gal1) gene in gliomas inhibited invasivity in vitro and tumor formation in vivo. To identify other glycogene targets with therapeutic potential, we created a focused 45-mer oligonucleotide microarray platform representing all of the cloned human glycotranscriptome and examined the glycogene expression profiles of 10 normal human brain specimens, 10 malignant gliomas, and 7 human glioma cell lines. Among the many significant changes in glycogene expression observed, of particular interest was the observation that an additional α2,6-sialyltransferase, ST6 (α- N -acetyl-neuraminyl-2,3-β-galactosyl-1,3)- N -acetylgalactosaminide α2,6-sialyltransferase 5 (ST6GalNAcV), was expressed at very low levels in all glioma and glioma cell lines examined compared with normal brain. ST6GalNAcV catalyzes the formation of the terminal α2,6-sialic acid linkages on gangliosides. Stable transfection of ST6GalNAcV into U373MG glioma cells produced ( i ) no change in α2,6-linked sialic acid-containing glycoproteins, ( ii ) increased expression of GM2α and GM3 gangliosides and decreased expression of GM1b, Gb3, and Gb4, ( iii ) marked inhibition of in vitro invasivity, ( iv ) modified cellular adhesion to fibronectin and laminin, ( v ) increased adhesion-mediated protein tyrosine phosphorylation of HSPA8, and ( vi ) inhibition of tumor growth in vivo. These results strongly suggest that modulation of the synthesis of specific glioma cell-surface glycosphingolipids alters invasivity in a manner that may have significant therapeutic potential.