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)

Accumulating evidences that carcinogenesis requires multiple gene alterations of oncogenes and tumor suppressor genes have recently emerged. In addition, genes related to invasion and metastasis are also important in understanding development of colorectal cancer. In this study, clinical significance and application of tumor suppressor genes and invasion related genes such as APC (adenomatous polyposis coli), DCC (deleted in colorectal carcinoma) tumor suppressor genes and invasion related gene, matrilysin were studied. In the mouse tumor induced by mutagen contained in cooked food, PhIP (2-amino-1-methyl-6- phenylimidazo [4,5-b] pyridine), nonsense mutations of APC gene that is similar to human colorectal cancer have been observed. These results suggested the quite interesting issue of mutagen contained in daily food having etiological role of colorectal cancer. DCC gene alteration, decreased expression of DCC mRNA was detected in 60% of advanced colorectal cancer. In all cases with liver metastasis, DCC expression was absent or markedly decreased, a finding that detection of DCC expression have an clinical importance that predicts metastatic potential of colorectal cancer. Matrilysin, the member of MMPs (matrix metalloproteinases) which degrade matrix components such as type IV collagen, laminin or fibronectin. In most of colorectal cancer, matrilysin was overexpressed in tumor cells. Matrilysin-transfected colorectal cancer cells showed more invasive ability in vitro and gained metastatic potential in SCID mice. Suppression of matrilysin expression by treated with all-trans retinoic acid (ATRA) or introduction of anti-sense matrilysin decreased the invasive ability in vitro. This result suggests that matrilysin plays an important role in invasion and metastasis and have a possibility of new anti-invasion therapy.
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PMID:[Genetic diagnosis of colorectal cancer]. 872 69

Cancer mortality usually results from the tumor invading the local environment and metastasizing to vital organs, e.g. liver, lung, and brain. Degradation of the extracellular matrix is, therefore, the sine qua non of tumor cell invasion. this degradation is mediated mainly by MMPs, and thus, inhibition of MMP synthesis is a target for anticancer agents. Tumor cells must traverse both the basement membrane (type IV collagen) and the interstitial stroma (type I collagen). Therefore, we used scanning electron microscopy to examine the invasive behavior of several aggressive tumor cell lines, A2058 melanoma cells, and SCC and FaDu squamous cell carcinomas through these matrices; and we monitored the ability of all-trans retinoic acid and several RAR-specific ligands to block invasion. We demonstrate that several retinoids, which are specific RAR alpha, beta, or gamma agonists/antagonists, selectively inhibited MMP synthesis in the three tumor cell lines. However, there was not a common pattern of MMP inhibition by a particular retinoid. For instance, a RAR alpha antagonist suppressed MMP-1 and MMP-2 synthesis in the melanoma cell line, but not in the FaDu or SCC-25 cells. On the other hand, synthesis of MMP-1 and MMP-9 by the FaDu cells was affected hardly at all, while a RAR gamma antagonist reduced the levels of MMP-2. Only all-trans retinoic acid reduced MMP-1 synthesis in these cells. We postulate that the differences may be related to a differential pattern of RAR expression in each of these cells, and that the RARs expressed by each cell line may not be targets of these RAR specific compounds. All-trans retinoic acid is a pan ligand, binding to all three RARs and, therefore, may modulate gene expression more generally. We conclude that the power of these new ligands lies in their specificity, which can be directed towards modulating expression of certain RARs and, thus, of certain MMPs. By blocking MMP synthesis, retinoids may be effective in cancer therapy by decreasing tumor invasiveness.
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PMID:Retinoid-mediated suppression of tumor invasion and matrix metalloproteinase synthesis. 1041 49

The chondrocytes of articular cartilage synthesize a number of proteinases which are capable of degrading the component molecules of this specialized extracellular matrix. The use of class-specific proteinase inhibitors indicates that major activities responsible for catabolism of proteoglycan (aggrecan) and collagen are attributable to zinc-dependent metalloproteinases. In this study, we have compared the mRNA expression profiles of two matrix metalloproteinases (MMP-3 and MMP-13) and five disintegrin-metalloproteinases (ADAM-10, ADAM-9, ADAM-15, TNF-alpha-converting enzyme and decysin) by chondrocytes (human, porcine and bovine) from fresh cartilage and in cartilage explant cultures and isolated cells cultured in monolayer or in agarose gels. Such cultures were maintained in the presence or absence of interleukin-1 (IL-1) or all-trans-retinoic acid, two agents which promote cartilage matrix degradation in vitro. Whereas transcripts for all metalloproteinases examined were detected in chondrocytes from human osteoarthritic cartilage in monolayer cultures, mRNAs for ADAM-15 and decysin were not present in fresh osteoarthritic human cartilage or explant cultures. Similarly, expression of porcine and bovine metalloproteinase mRNAs varied with different culture conditions. Novel cDNA sequences obtained for porcine and bovine MMP-3 and MMP-13, porcine ADAM-10, porcine and bovine ADAM-9 and porcine TACE confirmed expression of mRNAs for these molecules by articular chondrocytes. Quantitative RT-PCR analysis was used to determine the effects of IL-1 and retinoic acid on metalloproteinase mRNA levels in human chondrocytes cultured in monolayer and in porcine chondrocytes cultured in agarose. For the MMPs, IL-1 treatment resulted in an approximately two to threefold increase in human and porcine MMP-3 and MMP-13 mRNAs, while retinoic acid treatment caused a statistically significant increase in human MMP-3 mRNA levels, but no significant change in transcript levels for porcine MMP-3 nor human or porcine MMP-13. The mRNA levels for ADAM-15 were elevated in human monolayer chondrocytes exposed to IL-1 or retinoic acid, while transcripts levels for TNF-alpha converting enzyme were increased in response to retinoic acid. In contrast, ADAM-9 mRNA levels were decreased in human monolayer chondrocytes exposed to IL-1 or retinoic acid. The results demonstrate that chondrocyte metalloproteinase expression can vary dependent on cell environment in situ and in vitro, and information on chondrocyte MMP and ADAM gene expression following cytokine (IL-1) or retinoid stimulation.
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PMID:Effects of culture conditions and exposure to catabolic stimulators (IL-1 and retinoic acid) on the expression of matrix metalloproteinases (MMPs) and disintegrin metalloproteinases (ADAMs) by articular cartilage chondrocytes. 1042 42

Along with degradation of type IV collagen in basement membrane, destruction of the stromal collagens, types I and III, is an essential step in the invasive/metastatic behavior of tumor cells, and it is mediated, at least in part, by interstitial collagenase 1 (matrix metalloproteinase 1 (MMP-1)). Because A2058 melanoma cells produce substantial quantities of MMP-1, we used these cells as models for studying invasion of type I collagen. With a sensitive and quantitative in vitro invasion assay, we monitored the ability of these cells to invade a matrix of type I collagen and the ability of a serine proteinase inhibitor and all-trans-retinoic acid to block invasion. Although these cells produce copious amounts of MMP-1, they do not invade collagen unless they are co-cultured with fibroblasts or with conditioned medium derived from fibroblasts. Our studies indicate that a proteolytic cascade that depends on stromal/tumor cell interactions facilitates the ability of A2058 melanoma cells to invade a matrix of type I collagen. This cascade activates latent MMP-1 and involves both serine proteinases and MMPs, particularly stromelysin 1 (MMP-3). All-trans-retinoic acid (10(-6) M) suppresses the invasion of tumor cells by several mechanisms that include suppression of MMP synthesis and an increase in levels of tissue inhibitor of metalloproteinases 1 and 2. We conclude that invasion of stromal collagen by A2058 melanoma cells is mediated by a novel host/tumor cell interaction in which a proteolytic cascade culminates in the activation of pro-MMP-1 and tumor cell invasion.
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PMID:A novel host/tumor cell interaction activates matrix metalloproteinase 1 and mediates invasion through type I collagen. 1046 64

The influence of all-trans retinoic acid (RA), either in its free or encapsulated form into wheat ceramides (CER), on the production of collagenase (MMP-1), and tissue inhibitor of metalloproteinase (TIMP-1) by human skin fibroblasts (HSF) at early and late stages of their proliferative life span (PLS) was examined. The level of MMP-1 was elevated and that of TIMP-1 decreased in late as compared to early passage cells. All-trans retinoic acid significantly decreased and increased the secretions of MMP-1 and TIMP-1 respectively, in a dose-dependent manner, from 10-7 m to 10-5 m. Entrapment of RA into CER vesicles potentiated its effect on MMP-1 and TIMP-1 secretions by HSF, independently of cell passages. The extent of variations obtained on MMP-1 and TIMP-1 levels, when HSF culture medium was supplemented with 10-5 m RA, could be obtained using a 100-fold lower concentration of RA encapsulated into CER vesicles. CER had no effect on TIMP-1 and MMP production by HSF in culture, and simultaneous addition of CER and RA did not potentiate the effects of RA alone, indicating that formation of RA-CER liposomes was responsible for the enhancing effects. The rate of internalization of RA into HSF was increased when used in its CER encapsulated form. Therefore, the use of retinoid within CER potentiates its beneficial influence on the MMP-1:TIMP-1 imbalance with fibroblastageing.
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PMID:Encapsulation of all-trans retinoic acid into wheat ceramides micro vesicles enhanced influence on collagenase and tissue inhibitor of metalloproteinase-1 production by human skin fibroblasts. 1850 19

Background. Vitamin A derivative all-trans retinoic acid (ATRA) is considered as a potent chemotherapeutic drug for its capability of regulating cell growth and differentiation. We studied the effect of ATRA on MMP-2 in MCF-7, human breast cancer cells, and the probable signaling pathways which are affected by ATRA on regulating pro-MMP-2 activity and expression. Methods. Gelatin zymography, RT-PCR, ELISA, Western blot, Immunoprecipitation, and Cell adhesion assay are used. Results. Gelatin zymography showed that ATRA caused a dose-dependent inhibition of pro-MMP-2 activity. ATRA treatment downregulates the expression of MT1-MMP, EMMPRIN, FAK, NF-kB, and p-ERK. However, expression of E-cadherin, RAR, and CRABP increased upon ATRA treatment. Binding of cells to extra cellular matrix (ECM) protein fibronectin reduced significantly after ATRA treatment. Conclusions. The experimental findings clearly showed the inhibition of MMP-2 activity upon ATRA treatment. This inhibitory effect of ATRA on MMP-2 activity in human breast cancer cells (MCF-7) may result due to its inhibitory effect on MT1-MMP, EMMPRIN, and upregulation of TIMP-2. This study is focused on the effect of ATRA on MMP, MMP-integrin-E-cadherin interrelationship, and also the effect of the drug on different signaling molecules which may involve in the progression of malignant tumor development.
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PMID:Studies on Multifunctional Effect of All-Trans Retinoic Acid (ATRA) on Matrix Metalloproteinase-2 (MMP-2) and Its Regulatory Molecules in Human Breast Cancer Cells (MCF-7). 1963 36