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

Roger A. Kroes, Huan He, Mark Emmett, Carol L. Nilsson, Franklin E. Leach, I. Jonathan Amster, Alan G. Marshall, Joseph R. Moskal

Research output: Contribution to journalArticle

43 Citations (Scopus)

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 lowlevels 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 gliomacells 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 tyrosinephosphorylationof 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 thatmay have significant therapeutic potential.

Original languageEnglish (US)
Pages (from-to)12646-12651
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number28
DOIs
StatePublished - Jul 13 2010
Externally publishedYes

Fingerprint

Sialyltransferases
Gangliosides
Glioma
Growth
N-Acetylneuraminic Acid
Neoplasms
Glycoproteins
G(M2) Ganglioside
G(M3) Ganglioside
Cell Line
Glycosphingolipids
Brain
Laminin
Oligonucleotide Array Sequence Analysis
Glycosylation
Fibronectins
Transfection
Neoplasm Metastasis
Therapeutics
Genes

Keywords

  • Glioblastoma
  • Glycosphingolipid
  • Glycosyltransferase
  • Glycosynapse
  • Heat shock 70 kDa protein 8

ASJC Scopus subject areas

  • General

Cite this

Overexpression of ST6GalNAcV, a ganglioside-specific α2,6- sialyltransferase, inhibits glioma growth in vivo. / Kroes, Roger A.; He, Huan; Emmett, Mark; Nilsson, Carol L.; Leach, Franklin E.; Amster, I. Jonathan; Marshall, Alan G.; Moskal, Joseph R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 28, 13.07.2010, p. 12646-12651.

Research output: Contribution to journalArticle

Kroes, Roger A. ; He, Huan ; Emmett, Mark ; Nilsson, Carol L. ; Leach, Franklin E. ; Amster, I. Jonathan ; Marshall, Alan G. ; Moskal, Joseph R. / Overexpression of ST6GalNAcV, a ganglioside-specific α2,6- sialyltransferase, inhibits glioma growth in vivo. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 28. pp. 12646-12651.
@article{ab765d873697401b808e25a1d3f6d1b1,
title = "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 lowlevels 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 gliomacells 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 tyrosinephosphorylationof 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 thatmay have significant therapeutic potential.",
keywords = "Glioblastoma, Glycosphingolipid, Glycosyltransferase, Glycosynapse, Heat shock 70 kDa protein 8",
author = "Kroes, {Roger A.} and Huan He and Mark Emmett and Nilsson, {Carol L.} and Leach, {Franklin E.} and Amster, {I. Jonathan} and Marshall, {Alan G.} and Moskal, {Joseph R.}",
year = "2010",
month = "7",
day = "13",
doi = "10.1073/pnas.0909862107",
language = "English (US)",
volume = "107",
pages = "12646--12651",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "28",

}

TY - JOUR

T1 - Overexpression of ST6GalNAcV, a ganglioside-specific α2,6- sialyltransferase, inhibits glioma growth in vivo

AU - Kroes, Roger A.

AU - He, Huan

AU - Emmett, Mark

AU - Nilsson, Carol L.

AU - Leach, Franklin E.

AU - Amster, I. Jonathan

AU - Marshall, Alan G.

AU - Moskal, Joseph R.

PY - 2010/7/13

Y1 - 2010/7/13

N2 - 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 lowlevels 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 gliomacells 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 tyrosinephosphorylationof 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 thatmay have significant therapeutic potential.

AB - 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 lowlevels 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 gliomacells 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 tyrosinephosphorylationof 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 thatmay have significant therapeutic potential.

KW - Glioblastoma

KW - Glycosphingolipid

KW - Glycosyltransferase

KW - Glycosynapse

KW - Heat shock 70 kDa protein 8

UR - http://www.scopus.com/inward/record.url?scp=77955462802&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955462802&partnerID=8YFLogxK

U2 - 10.1073/pnas.0909862107

DO - 10.1073/pnas.0909862107

M3 - Article

VL - 107

SP - 12646

EP - 12651

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 28

ER -