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)

Membrane type 1 (MT1) matrix metalloproteinase (MMP-14) is a membrane-tethered MMP considered to be a major mediator of pericellular proteolysis. MT1-MMP is regulated by a complex array of mechanisms, including processing and endocytosis that determine the pool of active proteases on the plasma membrane. Autocatalytic processing of active MT1-MMP generates an inactive membrane-tethered 44-kDa product (44-MT1) lacking the catalytic domain. This form preserves all other enzyme domains and is retained at the cell surface. Paradoxically, accumulation of the 44-kDa form has been associated with increased enzymatic activity. Here we report that expression of a recombinant 44-MT1 (Gly(285)-Val(582)) in HT1080 fibrosarcoma cells results in enhanced pro-MMP-2 activation, proliferation within a three-dimensional collagen I matrix, and tumor growth and lung metastasis in mice. Stimulation of pro-MMP-2 activation and growth in collagen I was also observed in other cell systems. Expression of 44-MT1 in HT1080 cells is associated with a delay in the rate of active MT1-MMP endocytosis resulting in higher levels of active enzyme at the cell surface. Consistently, deletion of the cytosolic domain obliterates the stimulatory effects of 44-MT1 on MT1-MMP activity. In contrast, deletion of the hinge turns the 44-MT1 form into a negative regulator of enzyme function in vitro and in vivo, suggesting a key role for the hinge region in the functional relationship between active and processed MT1-MMP. Together, these results suggest a novel role for the 44-kDa form of MT1-MMP generated during autocatalytic processing in maintaining the pool of active enzyme at the cell surface.
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PMID:The inactive 44-kDa processed form of membrane type 1 matrix metalloproteinase (MT1-MMP) enhances proteolytic activity via regulation of endocytosis of active MT1-MMP. 1841 12

Cathepsin D (CD) up-regulation has been associated with human malignancy and poor prognosis. Thrombin up-regulated CD mRNA and protein in eight tumor cell lines as well as in human umbilical vascular endothelial cells (HUVEC). Thrombin increased the secretion of CD by 3- to 8-fold and enhanced chemotaxis ( approximately 2-fold) in 4T1 murine mammary CA cells, which was completely inhibited with the knockdown of CD. Secreted 4T1 CD induced neoangiogenesis by 2.4-fold on a chick chorioallantoic membrane, which was blocked in CD-KD cells. The addition of pure CD (2 ng) to the chick chorioallantoic membrane increased angiogenesis by 2.1-fold, which was completely inhibited by Pepstatin A (Pep A). CD enhanced human HUVEC chemotaxis and Matrigel tube formation by 2-fold, which was then blocked by Pep A. CD enhanced HUVEC matrix metalloproteinase 9 (MMP-9) activity by approximately 2-fold, which was completely inhibited by Pep A as well as a generic MMP inhibitor, GM6001. The injection of CD-KD 4T1 cells into syngeneic mice inhibited tumor growth by 3- to 4-fold compared with empty vector (EV) cells. Hirudin, a specific thrombin inhibitor, inhibited the growth of wild-type and EV cells by 2- to 3-fold, compatible with thrombin up-regulation of CD. CD and thrombin also contributed to spontaneous pulmonary metastasis; 4-fold nodule inhibition with CD versus EV and 4.6-fold inhibition with hirudin versus EV (P < 0.02). Thus, thrombin-induced CD contributes to the malignant phenotype by inducing tumor cell migration, nodule growth, metastasis, and angiogenesis. CD-induced angiogenesis requires the proteolytic activation of MMP-9.
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PMID:Thrombin up-regulates cathepsin D which enhances angiogenesis, growth, and metastasis. 1855 12

Pericellular proteolysis of the extracellular matrix by membrane type 1-matrix metalloproteinase (MT1-MMP) confers tumor cells with the ability to proliferate within three-dimensional (3D) matrices and sustains tumor growth in mice. In this study, we show that in addition to its matrix-degrading activity, phosphorylation of MT1-MMP on its unique tyrosine residue located within its cytoplasmic sequence (Tyr573) may also participate to these processes. Fibrosarcoma cells expressing a proteolytically active but non-phosphorylable mutant of MT1-MMP showed a markedly reduced proliferation rate when embedded within 3D type I collagen matrices, this antiproliferative effect being correlated with arrest in the G(0)/G(1) phase of the cell cycle. Impaired tyrosine phosphorylation of MT1-MMP also inhibits anchorage-independent growth of HT-1080 cells in soft agar as well as their invasion of collagen barriers, two prominent attributes of tumor cells, suggesting a broad inhibitory effect of the MT1-MMP mutant on tumorigenesis. Accordingly, whereas HT-1080 cells formed well-vascularized tumors containing tyrosine-phosphorylated MT1-MMP, tumor growth was completely abolished by expression of the non-phosphorylable MT1-MMP mutant. These findings thus indicate a close co-operation between the matrix-degrading activity of MT1-MMP and tyrosine phosphorylation of its intracellular domain for tumor cell invasion and proliferation and suggest that the targeting of the intracellular signaling pathways leading to tyrosine phosphorylation of MT1-MMP may represent an unexpected alternative strategy for the inhibition of this enzyme.
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PMID:Impaired tyrosine phosphorylation of membrane type 1-matrix metalloproteinase reduces tumor cell proliferation in three-dimensional matrices and abrogates tumor growth in mice. 1862 44

Recent studies have demonstrated the efficacy of targeted therapy combined with radiotherapy in head and neck squamous cell carcinoma (HNSCC). We hypothesized that a combination treatment including a replicating adenovirus armed with tissue inhibitor of metalloproteinase-2 (TIMP-2), radiation and Cisplatin will augment treatment response and reduce tumor growth in vivo of HNSCC xenografts. Both single-agent (TIMP-2 virus, radiation and Cisplatin) and the combination therapies were evaluated in vitro and in vivo. The efficacy of both single-agent and combination therapies in vivo was determined by monitoring tumor growth and immunohistochemistry. Treatment with replicative Ad-TIMP-2 virus and radiation decreased cell viability in vitro and resulted in an additional antiangiogenic response in vivo. Tumor response rates to treatment with replicative Ad-TIMP-2, radiation, Cisplatin or combination therapies ranged from limited inhibition of tumor growth of the single-agent therapy to a statistically significant additive antitumor response with the combination therapies. Replicative Ad-TIMP-2+radiation+Cisplatin in the SCC1 nude mice demonstrated the greatest response rates in tumor growth and angiogenesis. Combination of Ad-TIMP-2 gene therapy with radiation and the triple treatment group resulted in an augmented therapeutic response. This is the first report of the potential benefits of combining radiation and MMP inhibitor treatment.
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PMID:Therapy of head and neck squamous cell carcinoma with replicative adenovirus expressing tissue inhibitor of metalloproteinase-2 and chemoradiation. 1884 12

Transforming growth factor-beta1 (TGF-beta1) promotes cancer progression by regulating tumor cell growth and angiogenesis and high levels of TGF-beta1 have been associated with metastatic disease and poor prognosis in breast cancer patients. We have previously reported anti-angiogenic effects of the anti-estrogen tamoxifen in breast cancer, by increased matrix metalloproteinase-9 (MMP-9) activity and generation of endostatin. Here, we show that exposure of tamoxifen to ER-positive breast cancer cells for 7 days, decreased extracellular TGF-beta1. Intracellular TGF-beta1 levels were unaffected by tamoxifen treatment, indicating a post-translational regulation of TGF-beta1. Inhibition of MMP activity restored TGF-beta1 levels, suggesting an involvement of MMP activities in the down-regulation of TGF-beta1 by tamoxifen. Moreover, using an in vivo model of solid MCF-7 tumors in nude mice, we analyzed tumor levels of TGF-beta1 after in vivo treatment with estradiol and tamoxifen. Exposure of tumor-bearing mice to tamoxifen significantly decreased tumor TGF-beta1 protein levels, tumor growth and angiogenesis. In conclusion, our findings suggest a novel mechanism of action of tamoxifen in breast cancer via sex steroid dependent modulation of the proteolytic tumor microenvironment resulting in reduced extracellular TGF-beta1 levels.
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PMID:Tamoxifen decreases extracellular TGF-beta1 secreted from breast cancer cells--a post-translational regulation involving matrix metalloproteinase activity. 1899 14

Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and molecular components of procoagulant pathways have been recently emerging as critical players of tumor growth and metastasis. In particular, thrombin, through the activity of its receptor protease-activated receptor-1 (PAR-1), regulates tumor cell adhesion to platelets and endothelial cells, stimulates tumor angiogenesis, and promotes tumor growth and metastasis. Notably, in many tumor types including melanoma, PAR-1 expression directly correlates with their metastatic phenotype and is directly responsible for the expression of interleukin-8, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor, platelet-derived growth factor, and integrins. Another proinflammatory receptor-ligand pair, platelet-activating factor (PAF) and its receptor (PAFR), have been shown to act as important modulators of tumor cell adhesion to endothelial cells, angiogenesis, tumor growth and metastasis. PAF is a bioactive lipid produced by a variety of cells from membrane glycerophospholipids in the same reaction that releases arachidonic acid, and can be secreted by platelets, inflammatory cells, keratinocytes and endothelial cells. We have demonstrated that in metastatic melanoma cells, PAF stimulates the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), which results in overexpression of MMP-2 and membrane type 1-MMP (membrane type 1-MMP). Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that metastatic melanoma cells are better equipped than their non-metastatic counterparts to respond to PAF within the tumor microenvironment. The evidence supporting the hypothesis that the two G-protein coupled receptors, PAR-1 and PAFR, contribute to the acquisition of the metastatic phenotype of melanoma is presented and discussed.
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PMID:Emerging roles of PAR-1 and PAFR in melanoma metastasis. 1930 89

This study was conducted to examine the polyamine transporter (PAT) recognization and antitumor effects of anthracenymethyl homospermidine (ANTMHspd) and its apoptotic mechanism in B16 melanoma cells. ANTMHspd promoted a dose-dependent apoptosis in B16 melanoma cells and the apoptosis was associated with the excellent PAT recognization, externalization of cell membrane phosphatidylserine and the disruption of mitochondria, these processes were correlated with up-regulation of polyamine oxidase, an increase in intracellular reactive oxygen species (ROS) production and oxidative stress. In addition, reduction of MMP, release of cytochrome c, up-regulation of Bax protein expression, down-regulation of Bcl-2 protein expression, and activation of caspase-3, caspase-9 were also observed in B16 cells after treatment with ANTMHspd. Furthermore, N-acetylcysteine obviously antagonized ANTMHspd-induced apoptosis. Importantly, ANTMHspd was found to be better tolerated and revealed potent antitumor effect on inhibiting tumor growth in situ and suppressing pulmonary metastasis in xenograft mice model. These data demonstrate that ANTMHspd is an excellent PAT recognization and potent antitumor agent.
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PMID:Polyamine transporter recognization and antitumor effects of anthracenymethyl homospermidine. 1959 33

Tissue inhibitor of metalloproteinase-2 (TIMP-2), the endogenous inhibitor of matrix metalloproteinase-2 (MMP-2), regulates tumor invasion by modulating the activity of MMP-2. In addition, TIMP-2 is involved in the direct regulation of cell growth and angiogenesis, independent of MMP inhibition. Therefore, the development of therapeutic agents that increase TIMP-2 levels may offer a novel and broad approach to anti-neoplastic therapy. We report that a novel small molecule synthetic flavanoid SR13179, which inhibits the invasion of a highly metastatic human breast cancer cell line MCF-10CA1a through Matrigel, significantly increases protein and mRNA levels of TIMP-2 in a time- and dose-dependent manner. SR13179 inhibits the gelatinolytic activity of MMP-2 by >50% but has no effect on MMP-2 protein expression. SR13179 also possesses potent anti-tumor activity in several tumor cell lines regardless of their hormone receptor, p53 or multi-drug resistance status. Given the multifunctional inhibitory activity of TIMP-2 on tumor growth and invasion, the observed increase in TIMP-2 expression by SR13179 may play a central role in the anti-tumor and anti-invasive activity of this novel small molecule. Modulation of TIMP-2 protein expression may be a new molecular target for anti-metastatic adjuvant therapy for breast and other cancers.
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PMID:Increase in tissue inhibitor of metalloproteinase-2 (TIMP-2) levels and inhibition of MMP-2 activity in a metastatic breast cancer cell line by an anti-invasive small molecule SR13179. 1975 65

Although recent data may provide theoretical support for the preventive use of antidepressants in cancer patients, so far no study has demonstrated the clinical benefits of such strategies in the general population of cancer patients [39, 41]. Moreover, an association between antidepressant use and the risk of tumor promotion could neither be excluded nor established. The aim of this study was to compare the effect of desipramine (a tricyclic antidepressant, TCA) and fluoxetine (a selective serotonin reuptake inhibitor, SSRI) on tumor growth of the mouse B16F10 transplanted melanoma in "young" 6-9 month old and "aged" 18-23 month old male C57BL/6 mice. Drugs were administered daily at a dose of 10 mg/kg, ip, for two weeks and tumor cells were inoculated 2 h after the last antidepressant administration. Control animals were treated with saline. Tumor growth was significantly slower in aged than in young saline-treated control animals. Pretreatment with desipramine dramatically promoted metastasis formation and increased mortality rate but inhibited primary tumor growth in young males. On the other hand, both antidepressants increased primary tumor growth in aged animals, whereas metastasis was only moderately promoted. To determine the effect of antidepressant drug pretreatment and tumor progress on some parameters of cell-mediated immunity (proliferative activity and cytokine production by splenocytes) and angiogenesis, vascular endothelial growth factor (VEGF) and metalloproteinase (MMP)-9 plasma levels were established. The prometastatic effect of desipramine in young animals was connected with an increase of VEGF and MMP-9 plasma levels.
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PMID:Age-dependent stimulatory effect of desipramine and fluoxetine pretreatment on metastasis formation by B16F10 melanoma in male C57BL/6 mice. 2008 Dec 47

Matrix metalloproteinase-9 (MMP-9) strongly influences tumor development and metastasis. Using resistant (rMCF-7) and sensitive (sMCF-7) breast cancer lines we investigated the role of MMP-9 in cell migration (CM) and tubular network (TN) formation, two processes implied in tumor growth and metastasis. Our data demonstrate that MMP-9 which is critical for CM is necessary but not sufficient for TN formation and suggest a link between MDR1/P-gp and constitutive MMP-9. Both TN formation and CM are dependent on PKC and ERK1/2 pathways. This study reinforces the logic of combining therefore MMP inhibitors in cancer therapy, especially in patients with chemoresistance and invasion/metastasis.
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PMID:Matrix metalloproteinase-9 is required for tubular network formation and migration of resistant breast cancer cells MCF-7 through PKC and ERK1/2 signalling pathways. 2035 13


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