Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acquired abdominal aortic aneurysms are usually associated with a mural thrombus through which blood continues to flow. Some early data suggest that aneurysmal evolution correlates with the biological activity of the thrombus. Our hypothesis was therefore that the thrombus could adsorb blood components and store, release, and participate in the activation of proteases involved in aneurysmal evolution. For this purpose, we have explored both the metalloproteinase and fibrinolytic systems in the thrombus and the wall of human aneurysms. We have first investigated blood clot formation and lysis in vitro. Spontaneous clotting induces a release of promatrix metalloproteinase (pro-MMP)-9 into the serum that was fourfold higher than in paired control plasma (P < 0.001). Fibrinolysis progressively released more MMP-9 in a time-dependent manner (P < 0.01). After selective isolation, we demonstrated that polymorphonuclear leukocytes are the main source of MMP-9 release during clot formation. Protease content was then analyzed in 35 mural thrombi and walls of human abdominal aortic aneurysms sampled during surgical repair. In 15 aneurysms, the liquid phase at the interface between the thrombus and the wall was sampled separately. Both thrombus and wall contained MMP-2 and MMP-9 but the ratio MMP-9/MMP-2 was higher in the thrombus than in the wall. The liquid interface also contained active MMP-9. Immunohistochemistry of the thrombus confirmed these findings, showing the presence of polymorphonuclear leukocytes at the luminal pole of the thrombus, co-localizing with MMP-9 storage. In contrast, MMP-3 and MMP-7 were only present in the aneurysmal wall. Plasminogen was present in the mural thrombus but plasmin activity was present in both thrombus and wall. In the liquid interface, plasmin-alpha(2)-anti-plasmin complexes were detected demonstrating in vivo the activation of plasminogen. In contrast, u-PA and t-PA were detectable only in the wall, suggesting that plasminogen present in the thrombus could be activated by factors secreted by the arterial wall. This was demonstrated in vitro, in which co-incubation of thrombus and wall extracts generated plasmin in the presence of a fibrin matrix and activated MMPs. In conclusion, our study strongly suggests that the mural thrombus, by trapping polymorphonuclear leukocytes and adsorbing plasma components could act as a source of proteases in aneurysms that may play a critical role in enlargement and rupture.
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PMID:Involvement of the mural thrombus as a site of protease release and activation in human aortic aneurysms. 1241 17

It seems certain that COX-2 is related to tumor and some data suggested that COX-2 might have relation to tumor malignance and angiogenesis. In order to elucidate the relationship between COX-2 and tumor invasive and angiogenic ability, we transfected human transitional cell carcinoma (TCC) cell line, EJ, permanently with a COX-2 expression vector or the mock vector. The EJ-COX(2) cells, which overexpressed COX-2, acquired increased invasiveness and angiogenic ability by activation of VEGF, uPA, and MMP-2. Increased invasiveness and angiogenic ability were reversed by treatment with either selective COX-2 inhibitor, NS-398, or dual COX inhibitor, indomethacin. These results demonstrate that overexpression of COX-2 can lead to phenotypic changes that alter the metastatic and angiogenic potential of TCC cancer cells.
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PMID:Cyclooxygenase-2 increased the angiogenic and metastatic potential of tumor cells. 1247 Jun 62

MMP-2, MMP-9, and uPA have been previously described as important to the invasive and metastatic potential of human tumors, including breast, lung, glioblastoma, and prostate. We examined the activity of these proteases and the levels of their inhibitors (TIMP-1 and TIMP-2) in a series of human meningioma tissue samples. Normal brain tissue did not show elevated levels of uPA, MMP-2 or MMP-9 activity. Meningiomas showed a mild, to moderate to significantly high level of uPA, MMP-2, and MMP-9. However, no increase in TIMP-1 or TIMP-2 levels was detected. Immunohistochemistry confirmed the assay findings and localized these molecules to the cell surface. The findings provide evidence for elevated levels of uPA and MMPs in meningiomas and suggest a therapeutic target for minimizing the malignant propensity of meningiomas using protease inhibitors.
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PMID:Expression of matrix metalloproteinases, their inhibitors, and urokinase plasminogen activator in human meningiomas. 1252 24

The effect of CNTF and BDNF on a proteolytic complement instrumental to invasion and on differentiation was studied in two murine neuroblastoma clones, N1 and N7. At the membrane level, gelatinase MMP-2--mainly the activated form--was restrained by CNTF and BDNF to a residual 34% with both factors; membrane-type 1 MMP was down-regulated to 50% (10 h) and 34% (24 h) with both factors; and urokinase-type plasminogen activator was restrained mainly by BDNF to 70%. In the medium, the two gelatinases MMP-2 and MMP-9 were mainly in zymogen form: only MMP-2 was restrained in N1 cells, while only MMP-9 was restrained in N7 cells by both factors, single or in combination. These effects were paralleled by the induction of neurite outgrowth, which was more stimulated in the less differentiated clone. These dose-dependent and transient effects make CNTF and BDNF ideal candidates for constraining the potentially invasive behavior of nervous system tumors.
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PMID:Modulation of proteolytic potential and differentiation by CNTF and BDNF in two mouse neuroblastoma clones: relation to invasion. 1255 77

Bikunin (bik), a Kunitz-type protease inhibitor, also known as urinary trypsin inhibitor, is proposed as a main participant in the inhibition of tumor cell invasion and metastasis, possibly through the direct inhibition of cell-associated plasmin activity and suppression of urokinase-type plasminogen activator (uPA) mRNA expression. In the present study, we transfected the human ovarian carcinoma cell line HRA, highly invasive cells, with an expression vector harboring a cDNA encoding for human bik. Our study was designed to investigate the effect of bik overexpression and changes in tumor cell phenotype and invasiveness in the stably transfected clones. Bik gene transfection of HRA gave the following results: 1) transfection of HRA with the bik cDNA resulted in 5 variants stably expressing functional bik; 2) bik(+) clones exhibited a significantly reduced uPA mRNA expression as compared to the parental cells; 3) bikunin negatively regulates the ERK1/2 activity; 4) secretion-blocking treatments of bik(+) clones abrogated bik-mediated suppression of ERK1/2 activation and uPA expression; 5) the regulation of invasion seen in the HRA cells is mainly mediated by the uPA-plasmin-MMP-2 system; 6) transfection of HRA with the bik gene significantly reduced invasion, but not proliferation, adhesion, or migration relative to the parental cells; and 7) animals with bik(+) clones induced reduced peritoneal dissemination and long term survival. We conclude that transfection of HRA cells with the bik cDNA constitutively suppresses ERK1/2 activation, which results in inhibition of uPA expression and subsequently reduces dissemination of bik(+) clones.
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PMID:Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cell line by overexpression of bikunin. 1256 52

Age is an important factor in the development and spread of breast cancer. Stromal cells also contribute to breast cancer growth and metastasis through the production of extracellular matrix (ECM) modifiers such as urokinase type plasminogen activator (uPA), its receptor (uPAR), its inhibitors (PAI-1 and PAI-2), matrix metalloproteinases (MMPs), and growth factors, including the fibroblast and insulin-like growth factors (FGF's and IGF's). In the present study we have investigated whether breast fibroblasts aged in vitro through passage in culture display altered levels of the plasminogen activator system and growth factors that are known to modulate that system. With real-time RT-PCR we found that during passage human breast fibroblasts, whether derived from the tumour burden or from matched adjacent normal breast tissue, exhibited a consistent increase in PAI-1 and FGF-1 and a decrease in MMP-2 mRNA expression. In addition, in 5 out of 7 fibroblast strains we observed an induction of uPA expression in combination with a reduced IGF-1 expression. Interestingly, while during aging MMP-2 protein increased in all tumour-derived fibroblast strains, these protein levels were reduced in all normal tissue- derived fibroblasts. No other clear-cut age-dependent alterations were found in the all-together 25 factors investigated. We furthermore demonstrate in one tumour-derived fibroblast strain that the increases in uPA and PAI-1 mRNA and MMP-2 protein production are inversely related to the telomere length. Artificially increasing telomere length in this fibroblast strain by expressing human telomerase reverse transcriptase (hTERT) prevented senescence and resulted in late passage cultures with early passage uPA, PAI-1 and MMP-2 levels. Our results show that aging accompanied by telomere loss induces PAI-1 and FGF-1 mRNA expression in all breast fibroblast strains, increases uPA and decreases IGF-1 mRNA expression in a subset, and increases MMP-2 protein expression only in tumour-derived breast fibroblasts. These age-induced levels of PAI-1, FGF-1, uPA and MMP-2 in stromal breast fibroblast could contribute to breast cancer progression.
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PMID:Aging of stromal-derived human breast fibroblasts might contribute to breast cancer progression. 1257 21

The ethyl acetate (EA) fraction obtained from a methanol extract of Spatholobi caulis (Leguminosae) has been investigated for anti-metastatic activities in vitro. The EA fraction of Spatholobi caulis inhibited platelet aggregation induced by B16BL6 melanoma cells with an IC(50) of 50 microgram/mL. The EA fraction significantly inhibited HT1080 cancer cell invasion through a matrigel-coated filter with an IC(50) of 25 microgram/mL. Messenger RNA expression of uPA was effectively decreased in HT1080 cells by the EA fraction of Spatholobi caulis with an IC(50) of 30 microgram/mL, but the expressions of MMP-2 (matrix metalloproteinase) and TIMPs (tissue inhibitors of metalloproteinases) were not changed. These findings indicated that the EA fraction suppressed tumour cell invasion by downregulation of uPA (urokinase-type plasminogen activator). Taken together, these results suggest that the EA fraction of Spatholobi caulis may have anti-metastatic activities by blocking tumour cell-induced platelet aggregation (TCIPA) and tumour cell invasion.
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PMID:Effects of the ethyl acetate fraction of Spatholobi caulis on tumour cell aggregation and migration. 1260 81

In search for new anticancer agents, we have evaluated the antiinvasive and antimigrative properties of recently developed synthetic coumarin derivatives among which two compounds revealed important activity: 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate and 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate. Both drugs were able to inhibit cell invasion markedly in a Boyden chamber assay, the bromo derivative being more potent than the reference matrix metalloprotease (MMP) inhibitor GI 129471. In vivo, tumour growth was reduced when nude mice grafted with HT1080 or MDA-MB231 cells were treated i.p. 3 days week(-1) with the bromo coumarin derivative. These effects were not associated with the inhibition of urokinase, plasmin, MMP-2 or MMP-9. The mechanism of action of the drugs remains to be elucidated. However, these two coumarin derivatives may serve as new lead compounds of an original class of antitumour agents.
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PMID:3-Bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate inhibits cancer cell invasion in vitro and tumour growth in vivo. 1267 13

Medial degeneration of extracellular matrix (ECM) proteins in the wall of abdominal aortas results in smooth muscle cell destruction, a loss of architectural integrity, and abdominal aortic aneurysm (AAA) formation. It has been theorized that an imbalance between proteinases and their naturally occurring inhibitors is the cause of these observed histologic abnormalities. Therefore, the purpose of this investigation was to determine if differences in the matrix metalloproteinase (MMP) -2 and -9, tissue inhibitor of metalloproteinase-1 (TIMP-1), tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA) protein and activity levels existed between infrarenal AAA and normal abdominal aortic tissue specimens. Between November 1995 and January 1997, 10 patients undergoing elective infrarenal AAA repair had a portion of their aneurysm walls snap frozen in liquid nitrogen and processed for subsequent western blot or zymographic analysis. Tissue specimens from 6 normal abdominal aortas obtained from fresh cadaver specimens were similarly processed and served as controls. Protein levels for MMP-2, MMP-9, TIMP-1, uPA, and tPA were analyzed by western blotting. The degree of MMP-2 and MMP-9 gelatinolytic activity was analyzed by zymography. Detection and immunolocalization for MMP-2, MMP-9 and CD68 was performed on tissue sections of AAA and normal infrarenal abdominal aortas fixed in 10% formalin. MMP-9 and tPA protein levels were increased in AAAs compared to controls by western blotting. However, uPA levels were slightly increased in controls. No differences in TIMP-1 protein levels were identified. Similarly, zymography demonstrated increased MMP-2 and MMP-9 gelatinolytic activity in AAAs compared to controls (p < or = 0.05). CD68-positive cells (macrophages) in the adventitia and media demonstrated immunoreactivity to MMP-9. This investigation demonstrated increased MMP-9 proteinase activity and tPA protein levels in the walls of AAAs, as well as inflammatory leukocyte invasion of the adventitia and media compared to controls. These data suggest that leukocyte-derived MMP-9 is associated with aortic wall degeneration and aneurysm formation. Furthermore, activation of MMP-9 may be caused by increased tPA levels in the walls of AAAs.
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PMID:Matrix metalloproteinase expressions in arteriosclerotic aneurysmal disease. 1270 18

Flavonoids have been proposed to act as chemopreventive agents in numerous epidemiological studies and have been shown to inhibit angiogenesis and proliferation of tumor cells and endothelial cells in vitro. Angiogenesis requires tightly controlled extracellular matrix degradation mediated by extracellular proteolytic enzymes including matrix metalloproteinases (MMPs) and serine proteases, in particular, the urokinase-type plasminogen activator (uPA)-plasmin system. In this study, we have investigated the antiangiogenic mechanism of the flavonoids, genistein, apigenin, and 3-hydroxyflavone in a human umbilical vein endothelial cell (HUVEC) model. The stimulation of serum-starved HUVECs with vascular endothelial growth factor/basic fibroblast growth factor (VEGF/bFGF) caused marked increase in MMP-1 production and induced the pro-MMP-2 activation accompanied by the increase in MT1-MMP expression. However, pretreatment with flavonoids before VEGF/bFGF stimulation completely abolished the VEGF/bFGF-stimulated increase in MMP-1 and MT1-MMP expression and pro-MMP-2 activation. Genistein blocked VEGF/bFGF-stimulated increase in TIMP-1 expression and decrease in TIMP-2 expression. Apigenin and 3-hydroxyflavone further decreased TIMP-1 expression below basal level and completely abolished TIMP-2 expression. VEGF and bFGF stimulation also significantly induced uPA expression, most strikingly the level of 33 kDa uPA, and increased the expression of PA inhibitor (PAI)-1. Genistein, apigenin, and 3-hydroxyflavone effectively blocked the generation of 33 kDa uPA, and further decreased the activity of the 55 kDa uPA and the expression of PAI-1 below the basal level. In conclusion, these data suggest that genistein, apigenin, and 3-hydroxyflavone inhibit in vitro angiogenesis, in part via preventing VEGF/bFGF-induced MMP-1 and uPA expression and the activation of pro-MMP-2, and via modulating their inhibitors, TIMP-1 and -2, and PAI-1.
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PMID:Flavonoids inhibit VEGF/bFGF-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases. 1276 86


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