Inhibition of Membrane Type-1 Matrix Metalloproteinase by Cancer Drugs Interferes with the Homing of Diabetogenic T Cells into the Pancreas

University of Bristol, Bristol, England, United Kingdom
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2005; 280(30):27755-8. DOI: 10.1074/jbc.M506016200
Source: PubMed


We have discovered that clinically tested inhibitors of matrix metalloproteinases can control the functional activity of T cell membrane type-1 matrix metalloproteinase (MT1-MMP) and the onset of disease in a rodent model of type 1 diabetes in non-obese diabetic mice. We determined that MT1-MMP proteolysis of the T cell surface CD44 adhesion receptor affects the homing of T cells into the pancreas. We also determined that both the induction of the intrinsic T cell MT1-MMP activity and the shedding of cellular CD44 follow the adhesion of insulin-specific, CD8-positive, Kd-restricted T cells to the matrix. Conversely, inhibition of these events by AG3340 (a potent hydroxamate inhibitor that was widely used in clinical trials in cancer patents) impedes the transmigration of diabetogenic T cells into the pancreas and protects non-obese diabetic mice from diabetes onset. Overall, our studies have divulged a previously unknown function of MT1-MMP and identified a promising novel drug target in type I diabetes.

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Available from: Alexei Y Savinov, Nov 18, 2015
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    • "Rather, gelatinase activity was associated with healthy, insulin-producing portions of the islets. The upregulation of MMP-14 is consistent with its proposed role in T-cell extravasation into the pancreas via CD44 cleavage (41) but can be excluded as a candidate for degradation of the peri-islet capsule. The upregulation of several protease inhibitors, including tissue inhibitor of metalloproteinases-2 and the serpins (α1-antitrypsin members), broad specificity proteinase inhibitors, suggests a compensatory mechanism to counteract the destructive effect of proteases (33), the balance of which probably controls whether the peri-islet BM can be penetrated. "
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    ABSTRACT: We provide the first comprehensive analysis of the extracellular matrix (ECM) composition of peri-islet capsules, composed of the peri-islet basement membrane (BM) and subjacent interstitial matrix (IM), in development of type 1 diabetes in NOD mice and in human type 1 diabetes. Our data demonstrate global loss of peri-islet BM and IM components only at sites of leukocyte infiltration into the islet. Stereological analyses reveal a correlation between incidence of insulitis and the number of islets showing loss of peri-islet BM versus islets with intact BMs, suggesting that leukocyte penetration of the peri-islet BM is a critical step. Protease- and protease inhibitor-specific microarray analyses (CLIP-CHIP) of laser-dissected leukocyte infiltrated and noninfiltrated pancreatic islets and confirmatory quantitative real time PCR and protein analyses identified cathepsin S, W, and C activity at sites of leukocyte penetration of the peri-islet BM in association with a macrophage subpopulation in NOD mice and human type 1 diabetic samples and, hence, potentially a novel therapeutic target specifically acting at the islet penetration stage. Interestingly, the peri-islet BM and underlying IM are reconstituted once inflammation subsides, indicating that the peri-islet BM-producing cells are not lost due to the inflammation, which has important ramifications to islet transplantation studies.
    Full-text · Article · Nov 2012 · Diabetes
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    • "As movement takes place, CD44's anchorage of the cell's uropod to the ECM is disengaged by proteolytic activity. Cleavage of the extracellular domain of CD44 is mediated by membrane type metalloproteinases on responding T cells (Savinov et al., 2005). The development of cell polarity depends upon remodeling of the actin cytoskeleton that is regulated by the Rho family of GTPases (Tybulewicz and Henderson, 2009). "
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    ABSTRACT: Despite the widespread use of the cell-surface receptor CD44 as a marker for antigen (Ag)-experienced, effector and memory T cells, surprisingly little is known regarding its function on these cells. The best-established function of CD44 is the regulation of cell adhesion and migration. As such, the interactions of CD44, primarily with its major ligand, the extracellular matrix (ECM) component hyaluronic acid (HA), can be crucial for the recruitment and function of effector and memory T cells into/within inflamed tissues. However, little is known about the signaling events following engagement of CD44 on T cells and how cooperative interactions of CD44 with other surface receptors affect T cell responses. Recent evidence suggests that the CD44 signaling pathway(s) may be shared with those of other adhesion receptors, and that these provide contextual signals at different anatomical sites to ensure the correct T cell effector responses. Furthermore, CD44 ligation may augment T cell activation after Ag encounter and promote T cell survival, as well as contribute to regulation of the contraction phase of an immune response and the maintenance of tolerance. Once the memory phase is established, CD44 may have a role in ensuring the functional fitness of memory T cells. Thus, the summation of potential signals after CD44 ligation on T cells highlights that migration and adhesion to the ECM can critically impact the development and homeostasis of memory T cells, and may differentially affect subsets of T cells. These aspects of CD44 biology on T cells and how they might be modulated for translational purposes are discussed.
    Full-text · Article · Feb 2012 · Frontiers in Immunology
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    • "Detailed studies by RNA interference recently revealed that MT1-MMP also controls mesenchymal stromal cell mobilization and homing processes, which require invasion through ECM barriers [17] [18] and which may possibly contribute to brain tumor development [19]. In addition, previous demonstration that MT1-MMP can function as an activator of latent proM- MP-2 [20] was later strengthened by demonstrations that reduced activation of proMMP-2 was observed in various tissues of MT1-MMP null mice [21] and that inhibition of MT1-MMP by cancer drugs interfered with the homing of diabetogenic T cells into the pancreas [22]. Because of MT1-MMP's ability to promote directed cell migration across reconstituted basement membranes both in metastasis and in tumor angiogenesis processes, newly developed oncogenic strategies, including specific immunoliposomal anticancer MT1-MMP targeting [23] and interference RNA technology [24] are currently under consideration . "
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    ABSTRACT: Recent profiling has identified the aminopeptidase N/CD13 inhibitor actinonin as a selective soluble secreted matrix metalloproteinase (MMP) inhibitor. Given that actinonin's effects against membrane-bound MMPs remain unknown and that MT1-MMP has been linked to chemo- and radio-therapy resistance in brain tumor development, we therefore assessed MT1-MMP functional inhibition by actinonin in U87 glioblastoma cells. We show that actinonin inhibits concanavalin-A (ConA)-induced proMMP-2 activation, while it does not inhibit ConA-induced MT1-MMP gene expression suggesting post-transcriptional effects of the drug possibly mediated through the membrane-anchored protease regulator RECK. Specific gene silencing of MT1-MMP with siRNA abrogated the ability of ConA to activate proMMP-2. Functional recombinant MT1-MMP whose constitutive expression led to proMMP-2 activation was also efficiently antagonized by actinonin. We provide evidence for actinonin's new therapeutic application in the direct targeting of MT1-MMP-mediated proMMP-2 activation, an essential step in both brain tumor infiltration and in brain tumor-associated angiogenesis.
    Full-text · Article · Apr 2009 · Cancer letters
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