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Glycobiology Advance Access originally published online on December 8, 2007
Glycobiology 2008 18(2):195-204; doi:10.1093/glycob/cwm133
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© The Author 2008. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Tetra- and hexavalent mannosides inhibit the pro-apoptotic, antiproliferative and cell surface clustering effects of concanavalin-A: Impact on MT1-MMP functions in marrow-derived mesenchymal stromal cells

Simon Fortier3,2, Mohamed Touaibia2,4, Simon Lord-Dufour3, Jacques Galipeau5, René Roy3 and Borhane Annabi1,3

3 Équipe PharmaQÀM, Laboratoire d’Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, Quebec, Canada
4 Département de Chimie et Biochimie, Université de Moncton, Moncton, New-Brunswick, Canada
5 Department of Medicine, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada

1 To whom correspondence should be addressed: Tel: +1-514-987-3000 ext 7610; Fax: +1-514-987-0246; e-mail: annabi.borhane{at}uqam.ca

Received on October 2, 2007; revised on November 26, 2007; accepted on November 30, 2007

Mesenchymal stromal cells (MSC) mobilization and recruitment by experimental vascularizing tumors involves membrane type 1-matrix metalloproteinase (MT1-MMP) functions. Given that the mannose-specific lectin Concanavalin-A (ConA) induces MT1-MMP expression and mimics biological lectins/carbohydrate interactions, we synthesized and tested the potential of 11 mannoside clusters to block ConA activities on MSC. We found that tetra- and hexavalent mannosides reversed ConA-mediated changes in MSC morphology and antagonized ConA-induced caspase-3 activity and proMMP-2 activation. Tetra- and hexavalent mannosides also inhibited ConA- but not the cytoskeleton disrupting agent Cytochalasin-D-induced MT1-MMP cell surface proteolytic processing mechanisms, and effects on cell cycle phase progression. The antiproliferative and pro-apoptotic impact of ConA on the MT1-MMP/glucose-6-phosphate transporter signaling axis was also reversed by these mannosides. In conclusion, we designed and identified glycocluster constructions that efficiently interfered with carbohydrate-binding proteins (lectins) interaction with oligosaccharide moieties of glycoproteins at the cell surface of MSC. These glycoclusters may serve in carbohydrate-based anticancer strategies through their ability to specifically target MT1-MMP pleiotropic functions in cell survival, proliferation, and extracellular matrix degradation.

Key words: cancer / concanavalin-A / mannosides / mesenchymal stromal cells / MT1-MMP

2 These authors contributed equally to this work.


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