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.glycosyltransferase | glycosphingolipid | glioblastoma | heat shock 70 kDa protein 8 | glycosynapse

The presence and clinical implications of α-2,6-galactose-linked sialic acids in non-small-cell lung cancer brain metastases — preliminary study

“…The same concerns the influence of on cellular motility and invasive capabilities. For particular cell types overexpression of a-2,6-GalSA or a-2,6-ST enzyme has been associated with enhanced tumor migration potential (breast cancer cell line [22], colon cancer cell lines [23], HCC cell line [24]), whereas for other cell types this phenomenon results in impaired departure from the originating tissue (lymphosarcoma cell line MDAY-D2 [25]) and inhibition of tumor growth in vivo (glioma [26]). …”

Quantitative proteomics and transcriptomics reveals metabolic differences in attracting and non-attracting human-in-mouse glioma stem cell xenografts and stromal cells

“…Therefore, we hypothesized that alteration of the proteomic profile of cancer and stromal cell populations between attractor and non-attractor GSC xenografts may provide insights into key biochemical pathways involved in the attraction of BM-hMSCs to gliomas. We have previously performed label-free quantitative proteomic and targeted transcriptomic studies on GSCs and GBM cells [23][24][25][26]. For the first time, we extend these methodologies to attractor and non-attractor GSCXs.…”

Apoptosis of Breast Cancer Cells: Modulation of Genes for Glycoconjugate Biosynthesis and Targeted Drug Delivery

“…16.7 ) (Ma et al 2009(Ma et al , 2011Kessler et al 2007b ) . The glyco-related gene DNA-microarrays (Kroes et al 2011 ) , containing more than 300 different genes, also suggested (Tables 16.3 and 16.4 ) modulation of the transcriptional regulation (many were stimulated) of several GLTs involved in the biosynthesis of neolactosylceramide containing cell-surface antigens in these apoptotic breast carcinoma cells. In the early apoptotic stages (2-6 h after l -PPMP treatment) in addition to the GlcT-1 gene, several genes (betaGalTs and betaGlcNAcTs) in the SA-Lea pathway were stimulated (Tables 16.3 and 16.4 ).…”