Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinase (MMP) activity has been associated with tumor invasion and metastasis in many different tumor types, but recent studies also support a role for these enzymes in earlier stages of the tumor progression continuum. Specifically, the expression pattern of MMPs in benign human and mouse gastrointestinal tumors suggests that they may function in the development or growth of non-invasive tumors. To address the contribution of MMP activity to the development of intestinal adenomas, we administered the synthetic MMP inhibitor batimastat and expressed the tissue inhibitor of metalloproteinases-1 (TIMP-1) in the gastrointestinal tract of Min mice, which spontaneously develop pre-malignant small and large intestinal tumors. Batimastat administration resulted in a 48% decrease in the number of Min tumors. This reduction in tumor number is similar to that observed in mice lacking the metalloproteinase matrilysin, and demonstrates the therapeutic and chemopreventive potential of MMP inhibitors for pre-malignant intestinal tumors. In contrast, forced TIMP-1 expression in transgenic mice had no effect or, in one line, unexpectedly augmented Min tumor multiplicity by 32%. This observation supports an in vivo tumor-promoting activity of TIMP-1 that could be related to the growth stimulatory effects of TIMP that have been documented in vitro. Taken together, these 2 approaches of modulating MMP activity in Min mice support a critical function of MMPs in Min tumorigenesis, underscore the importance of an MMP/inhibitor balance in maintaining tissue homeostasis and demonstrate that endogenous MMP inhibitors can have complex effects in particular cellular contexts.
 ...
PMID:Differing effects of endogenous and synthetic inhibitors of metalloproteinases on intestinal tumorigenesis. 980 34

Normal wounds can heal by secondary intention (epidermal migration to cover a denuded surface) or by approximation of the wound edges (e.g., suturing). In healing by secondary intention, epidermis-derived MMPs are important. Keratinocyte migration begins within 3-6 hr post injury, as basal cells detach from underlying basal lamina and encounter a dermal substratum rich in type I collagen. Cell contact with type I collagen in vitro stimulates collagenase-1 expression, which is mediated by the alpha 2 beta 1 integrin, the major keratinocyte collagen-binding receptor. Collagenase-1 activity alone is necessary and sufficient for keratinocyte migration over a collagen subsurface. Stromelysins-1 and -2 are also found in the epidermis of normal acute wounds. Stromelysin-2 co-localizes with collagenase-1 and may facilitate cell migration over non-collagenous matrices of the dermis. In contrast, stromelysin-1 is expressed by keratinocytes behind the migrating front and which remain on basal lamina, i.e., the proliferative cell population. Studies with stromelysin-1-deficient mice that suggest this MMP plays a role in keratinocyte detachment from underlying basement membrane to initiate cell migration. In chronic ulcers, MMP levels are markedly elevated, in contrast to their precise temporal and spatial expression in acute wounds. Both collagenase-1 and stromelysin-1 are found in fibroblasts underlying the nonhealing epithelium, and stromelysin-1 expression is especially prominent. Two key questions underlie the use of MMP inhibitors and wound healing: (1) will these agents impair normal reepithelialization in wounds that heal by secondary intention; and (2) can MMP inhibitors be effective therapy for chronic ulcers? The answer to neither is known. Batimastat and marimastat appear not to interfere with normal wound healing, but only in sutured surgical wounds, a situation in which MMP expression has practically no role. We also show the first example of an in vivo immune response, contact hypersensitivity, which is dependent upon MMP activity. Using gene-deficient mice, we demonstrate that stromylysin-1 (MMP-3) is required for sensitization, whereas gelatinase B (MMP-9) is required for timely resolution of the reaction to antigenic challenge.
 ...
PMID:Role of matrix metalloproteinases and their inhibition in cutaneous wound healing and allergic contact hypersensitivity. 1041 17

Activation of matrix metalloproteinase-2 (MMP-2) by the membrane-type matrix metalloproteinases (MT-MMPs) has been associated with tumor progression. In the present study, we examined the role of MMP-2 and its activators MT1-MMP, MT2-MMP and MT3-MMP in pancreatic tumor cell invasion and the development of the desmoplastic reaction characteristic of pancreatic cancer tissues. Northern blot analyses revealed that transcript levels of MT1-MMP and MT2-MMP, but not MT3-MMP, were enhanced in pancreatic cancer tissues (n = 18) compared with both chronic pancreatitis (n = 9) and healthy pancreas (n = 9). A good correlation was found between MT1-MMP and both MMP-2 expression (p < 0.01) and activity in pancreatic cancer tissues. In addition, expression and activation of MMP-2 were strongly associated with the extent of the desmoplastic reaction in pancreatic cancer tissues. Invasion assays showed a good correlation between MMP-2 expression and activity and the invasive potential of pancreatic cancer cell lines. In cell lines with high levels of MMP-2 expression and activity, the MMP inhibitor Batimastat led to significant reduction of the number of invading cells. Our results suggest that MT1-MMP is involved in the progression of pancreatic cancer via activation of MMP-2. MMP-2 itself plays an important role in tumor cell invasion and appears to be associated with the development of the characteristic desmoplastic reaction in pancreatic cancer.
 ...
PMID:Role of MT-MMPs and MMP-2 in pancreatic cancer progression. 1058 76

Many studies have highlighted the role played by matrix metalloproteinases MMP-2 and -9, by serine proteases uPA and plasmin in tumor cell invasion. This study investigates the impact of the MMP-inhibitor Batimastat and/or the serine protease inhibitor Aprotinin on the in vitro proteolytic activity and in vivo invasive behavior the of esophageal (OC1) and ovarian (OVCAR-3) carcinoma cells. In presence and absence of inhibitors, proteolytic activity of the tumor cells was determined by caseinolytic and collagenolytic in vitro assays and tumor cell invasion by intraperitoneal inoculation of the tumor cells into nude mice. In vitro, Aprotinin, tested alone or in combination with Batimastat, efficiently inhibited degradation of collagen IV and casein by the tumor cells. Batimastat alone had no effect on caseinolytic activities and only partially blocked collagen-type-IV-degradation by the tumor cells. In vivo, Aprotinin tested alone or in combination with Batimastat did not prevent tumor cell invasion. Treatment of tumor bearing mice with Batimastat significantly inhibited tumor growth but promoted tumor cell invasion into the liver. Our findings demonstrate that the inhibition pattern of cellular proteolytic activity achieved in vitro by a serine protease and an MMP inhibitor may lead to predictions that are not necessarily verified in vivo and may even have adverse effects.
 ...
PMID:Combined treatment with serine protease inhibitor aprotinin and matrix metalloproteinase inhibitor Batimastat (BB-94) does not prevent invasion of human esophageal and ovarian carcinoma cells in vivo. 1062 17

To assess the contribution of the plasmin/matrix metalloproteinase cascade in lattices retraction, human gingival fibroblast-populated collagen lattices were supplemented with plasminogen. The rate of lattice retraction was enhanced by addition of plasminogen. This effect was concomitant to plasmin generation, prostromelysin-1 and procollagenase activation. Plasminogen-mediated initiation of that proteolytic cascade was accompanied by conspicuous changes in cell morphology and collagen fibers organization. At day 1 of culture fibroblasts shifted from a rounded (control) to an elongated (in presence of plgn) shape. At the latest stage of retraction, intense vacuolization around fibroblasts was noticed in plgn-supplemented lattices which paralleled the increased collagen degradation. Plgn-enhancing influence on the initial phase of lattice retraction could be totally annihilated by either aprotinin or Batimastat. Those data emphasize the crucial importance of the plasmin-MMP proteolytic cascade in granulation tissue retraction in a healing wound.
 ...
PMID:Contribution of the plasmin/matrix metalloproteinase cascade to the retraction of human fibroblast populated collagen lattices. 1086 Aug 66

The study of treatment-induced changes in the tumour microenvironment might lead to effective combinations of biological therapy. IL-12 induced tumour regression and cure of an experimental murine breast cancer, HTH-K, but only after long-term treatment that was associated with chronic toxicity. During IL-12 therapy, tumour levels of the matrix metalloprotease MMP-9 declined and its inhibitor TIMP-1 was strongly induced. We therefore administered alternate cycles of IL-12 and the MMP inhibitor Batimastat (BB94) to mice. Therapeutic efficacy was increased compared with short-term IL-12 therapy but without the chronic toxicity associated with long-term IL-12 treatment. Image analysis of treated tumours revealed that BB94 prevented regeneration of tumour and stromal compartments that normally occurred after short-term IL-12 therapy.
 ...
PMID:Exploiting changes in the tumour microenvironment with sequential cytokine and matrix metalloprotease inhibitor treatment in a murine breast cancer model. 1107 65

Collagenase-3 (MMP-13) is characterized by an exceptionally wide substrate specificity and restricted expression. MMP-13 is 1 of the few MMPs primarily expressed by tumor cells in malignant tumors, e.g., squamous cell carcinomas and its expression correlates with their invasion capacity. In this work, we have constructed an expression vector and a recombinant adenovirus harboring human MMP-13 cDNA to investigate the role of MMP-13 in cancer cell invasion. Our results show that constitutive expression of MMP-13 by HT-1080 cells stably transfected with MMP-13 expression vector or transduced with MMP-13 adenovirus markedly increased their invasion both through type I collagen and reconstituted basement membrane (Matrigel) with no alterations in expression or activation of collagenase-1 (MMP-1), gelatinase-A (MMP-2), or gelatinase-B (MMP-9). The enhanced invasion capacity of MMP-13 expressing HT-1080 cells was dependent on MMP activity, as it was blocked by MMP inhibitor Batimastat (BB-94) and tissue inhibitor of metalloproteinases-3 (TIMP-3). Our data provide direct evidence for the role of MMP-13 as a potent invasion proteinase, which alone can enhance the ability of malignant cells to penetrate through both basement membrane and fibrillar collagen.
 ...
PMID:Expression of collagenase-3 (MMP-13) enhances invasion of human fibrosarcoma HT-1080 cells. 1177 78

C18 unsaturated fatty acids were here found to inhibit proMMP (matrix metalloproteinase)-3 activation by plasmin. This effect was suppressed by lysine ligand competitors, indicating that it was mediated by binding to kringle domains. Surface plasmon resonance analysis demonstrated that oleic acid interacted to a similar extent with plasmin and kringle 5 (KD values of 3.4 x 10(-8) and 5.9 x 10(-8)M) while interaction with kringles 1-2-3 was 10-fold lower. Furthermore, oleic acid stimulated the amidolytic activity of plasmin and mini-plasmin, but not micro-plasmin. Oleic acid also enhanced u-PA (urokinase-type plasminogen activator)-mediated plasminogen activation over 50-fold. Taken together, these data indicate that inhibition of plasmin-induced proMMP-3 activation by unsaturated fatty acids was mediated through their preferential binding to kringle 5. The influence of elaidic acid on the plasmin/MMP-3/MMP-1 proteolytic cascade was assessed ex vivo. Exogenous addition of plasmin to dermal fibroblasts or supplementation of gingival fibroblast culture medium with plasminogen triggered this cascade. In both instances, elaidic acid totally abolished proMMP-3 and proMMP-1 activation. Additionally, a significant decrease in lattice retraction and collagen degradation in a range similar to that obtained with Batimastat was observed when human gingival fibroblasts were cultured in plasminogen-containing type I collagen gels, indicative of the dual influence of unsaturated fatty acids on MMP activation and activity. In conclusion, unsaturated fatty acids or molecules with similar structures could be attractive target for the development of natural pharmacological inhibitors directed against plasmin and/or MMPs in different pathological contexts such, skin UV irradiation, vascular diseases and tumour growth and invasion.
 ...
PMID:Inhibition of plasmin-mediated prostromelysin-1 activation by interaction of long chain unsaturated fatty acids with kringle 5. 1475 64

Elastin-derived peptides display a wide range of biological activities in a number of normal and transformed cells but their involvement in angiogenesis has not been reported. In the present study, we show that kappa-elastin and VGVAPG hexapeptide elastin motif accelerated angiogenesis in the chick chorio-allantoic membrane in an in vivo model. They also stimulated pseudotube formation from human vascular and microvascular endothelial cells in the matrigel and collagen models as well as cell migration in an in vitro wound healing assay. Confocal and scanning electron microscopy analyses revealed the main reorganization of actin filaments mediated by elastin-derived peptides and changes in cell shape that correlated with a decrease of the cell form factor determined by computerized image analysis. Such elastin-derived peptide effects were attributed to upregulation of proMT1-MMP and proMMP-2 expression and activation at both the mRNA and protein levels. Batimastat, an inhibitor of furin convertase and TIMP-2, but not TIMP-1, totally abolished the influence of elastin-derived peptides (EDPs) on cell migration and tubulogenesis, thus favoring the involvement of MT1-MMP in such processes. To assess its contribution to EDP-mediated angiogenesis further, we used a small interfering RNA (siRNA) approach for specifically silencing MT1-MMP in human microvascular endothelial cells. Four sets of 21 bp siRNA duplexes targeting MT1-MMP mRNA were synthesized by in vitro transcription. Two of them proved to inhibit MT1-MMP expression efficiently but did not affect MT2-, MT3- and MT5-MMP expression. Seventy-two hours after transfection with 25 nM siRNAs EDP-induced MT1-MMP expression at the mRNA and protein levels was decreased fourfold. In parallel, proMMP-2 activation was inhibited. A scrambled siRNA, used as a negative control, had no effect. Finally, the effect of elastin peptides on pseudotube formation in MT1-MMP-siRNA transfected cells was totally abolished. These data emphasise the crucial role of MT1-MMP in the elastin-induced angiogenic phenotype of endothelial cells.
 ...
PMID:Elastin-derived peptides enhance angiogenesis by promoting endothelial cell migration and tubulogenesis through upregulation of MT1-MMP. 1563 6

The degradation of biogenic amines by monoamine oxidase A (MAO-A) generates reactive oxygen species (ROS) which participate in serotonin and tyramine signaling. This study aimed to investigate the role of ROS in the mitogenic signaling activated during tyramine and serotonin oxidation by MAO-A in smooth muscle cells (SMC). Incubation of SMC with serotonin or tyramine induced intracellular ROS generation, and a signaling cascade involving metalloproteases and the neutral sphingomyelinase-2 (nSMase2, the initial step of the sphingolipid pathway), ERK1/2 phosphorylation, and DNA synthesis. Silencing MAO-A by siRNA, pharmacological MAO-A inhibitors (pargyline and Ro41-1049), and the antioxidant/ROS scavenger butylated hydroxytoluene (BHT) inhibited the signaling cascade, suggesting that ROS generated during tyramine oxidation by MAO-A are required. The MMP inhibitor Batimastat, MMP2-specific siRNA, and MMP2 deletion (MMP2(-/-) fibroblasts) blocked nSMase activation and SMC proliferation, suggesting a role for MMP2 in this signaling pathway. Silencing nSMase2 by siRNA did not inhibit ROS generation and MMP2 activation, but blocked SMC proliferation induced by tyramine, suggesting that nSMase2 is downstream MMP2. These findings demonstrate that H(2)O(2)-generated during tyramine oxidation by MAO-A triggers a stress-induced mitogenic signaling via the MMP2/sphingolipid pathway, which could participate in excessive remodeling and alteration of the vascular wall.
 ...
PMID:MAO-A-induced mitogenic signaling is mediated by reactive oxygen species, MMP-2, and the sphingolipid pathway. 1756 Oct 96


1 2 Next >>