title: MT1-MMP down-regulates the glucose 6-phosphate transporter expression in marrow stromal cells: a molecular link between pro-MMP-2 activation, chemotaxis, and cell survival.
abstract: Bone marrow-derived stromal cells (BMSC) are avidly recruited by experimental vascularizing tumors, which implies that they must respond to tumor-derived growth factor cues. In fact, BMSC chemotaxis and cell survival are regulated, in part, by the membrane type-1 matrix metalloproteinase (MT1-MMP), an MMP also involved in pro-MMP-2 activation and in degradation of the extracellular matrix (ECM). Given that impaired chemotaxis was recently observed in bone marrow cells isolated from a glucose 6-phosphate transporter-deficient (G6PT-/-) mouse model, we sought to investigate the potential MT1-MMP/G6PT signaling axis in BMSC. We show that MT1-MMP-mediated activation of pro-MMP-2 by concanavalin A (ConA) correlated with an increase in the sub-G1 cell cycle phase as well as with cell necrosis, indicative of a decrease in BMSC survival. BMSC isolated from Egr-1-/- mouse or MT1-MMP gene silencing in BMSC with small interfering RNA (siMT1-MMP) antagonized both the ConA-mediated activation of pro-MMP-2 and the induction of cell necrosis. Overexpression of recombinant full-length MT1-MMP triggered necrosis and this was signaled through the cytoplasmic domain of MT1-MMP. ConA inhibited both the gene and protein expression of G6PT, while overexpression of recombinant G6PT inhibited MT1-MMP-mediated pro-MMP-2 activation but could not rescue BMSC from ConA-induced cell necrosis. Cell chemotaxis in response to the tumorigenic growth factor sphingosine 1-phosphate was significantly abrogated in siMT1-MMP BMSC and in chlorogenic acid-treated BMSC. Altogether, we provide evidence for an MT1-MMP/G6PT signaling axis that regulates BMSC survival, ECM degradation, and mobilization. This may lead to optimized clinical applications that use BMSC as a platform for the systemic delivery of therapeutic or anti-cancer recombinant proteins in vivo.
authors.affiliation: Laboratoire d'Oncologie Moléculaire, Département de Chimie, Centre BIOMED, Université du Québec à Montréal, Québec H3C 3P8, Canada.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Currie
authors.forename: Simon
authors.initials: S
authors.lastname: Fortier
authors.forename: Asmaa
authors.initials: A
authors.lastname: Sina
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
authors.forename: Borhane
authors.initials: B
authors.lastname: Annabi
mesh_terms: D000818:Animals; D017920:Antiporters / Q000096:biosynthesis*; D001854:Bone Marrow Cells / Q000166:cytology*; D002633:Chemotaxis; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006877:Hydroxamic Acids; D007211:Indoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000737:chemistry; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D017154:Stromal Cells / Q000166:cytology*
chemical_list: D017920:Antiporters; D006877:Hydroxamic Acids; D007211:Indoles; D008246:Lysophospholipids; D009004:Monosaccharide Transport Proteins; D011994:Recombinant Proteins; C503532:Slc37a4 protein, mouse; C060506:sphingosine 1-phosphate; D019298:Glucose-6-Phosphate; D053511:Matrix Metalloproteinase 14; C119203:ilomastat; D013110:Sphingosine