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J. Biol. Chem., Vol. 282, Issue 11, 8142-8149, March 16, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/11/8142    most recent M610894200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Currie, J.-C. Articles by Annabi, B. Search for Related Content PubMed PubMed Citation Articles by Currie, J.-C. Articles by Annabi, B. Social Bookmarking                      What's this?

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^*

Jean-Christophe Currie, Simon Fortier, Asmaa Sina, Jacques Galipeau, Jian Cao^¶, and Borhane Annabi, Holds a Canada Research Chair in Molecular Oncology from the Canadian Institutes of Health Research¹

From the Laboratoire d'Oncologie Moléculaire, Département de Chimie, Centre BIOMED, Université du Québec à Montréal, Québec H3C 3P8, Canada, the Department of Medicine, Lady Davis Institute for Medical Research, Montreal, Québec H3T 1E2, Canada, and the ^¶Department of Medicine, State University of New York, Stony Brook, New York 11794

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.

Received for publication, November 27, 2006 , and in revised form, December 26, 2006.

^* This work was supported by a grant of the Natural Sciences and Engineering Research Council of Canada (NSERC) (to B. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Laboratoire d'Oncologie Moléculaire, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montréal, Québec H3C 3P8, Canada. Tel.: 514-987-3000 (ext. 7610); Fax: 514-987-0246; E-mail: annabi.borhane{at}uqam.ca.

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