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.
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.
Equipe PharmaQAM, Laboratoire d'ncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, Quebec, Canada.
Simon
S
Fortier
Mohamed
M
Touaibia
Simon
S
Lord-Dufour
Jacques
J
Galipeau
René
R
Roy
Borhane
B
Annabi
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D002236:Carbohydrate Conformation; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects; D003208:Concanavalin A / Q000037:antagonists & inhibitors; D008351:Mannans / Q000494:pharmacology; D008362:Mannosides / Q000737:chemistry / Q000494:pharmacology*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000037:antagonists & inhibitors; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
D000970:Antineoplastic Agents; D008351:Mannans; D008362:Mannosides; D061965:Matrix Metalloproteinase Inhibitors; D008934:Mitogens; D003208:Concanavalin A; D053148:Caspase 3; D053511:Matrix Metalloproteinase 14