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)

Although it has been shown that the cross-talk between osteoblasts and tumor cells stimulates proliferation and invasion of prostate carcinoma (PCa) cells, the molecular mechanisms underlying this event are largely unknown. In this study, we demonstrated that the PCa cells, PC3, derived from bone metastasis, undergo changes of their invasive capability if grown in the presence of osteoblast-derived conditioned media (OBCM). Specifically, they were able to organize tridimensional structures in Matrigel, such as large branching colonies, tube-like structures and clusters of proliferating cells, after treatment. At the ultrastructural level, we observed that PC3 cells grown in the presence of OBCM presented an increment of membrane activity with a blast of shed membrane vesicles from the cell surface. After 6 h of incubation, protein content was approximately 5-fold more elevated in vesicles isolated from PC3 cells cultured in OBCM than in unstimulated cultures. Gelatin zymography of vesicles collected from OBCM-treated PC3 cells showed an increment of lytic bands of MMP family members identified as pro-enzymatic and active forms of gelatinase A (MMP-2) and gelatinase B (MMP-9). By casein-plasminogen zymography, this latter culture also presented an elevated level of high-molecular weight urokinase plasminogen activator (HMW-uPA). Purified vesicles from OBCM-treated PC3 cells incubated with Matrigel cleaved its components more efficiently than vesicles from untreated PC3 cells. Collectively, these findings indicate that osteoblasts produce factor/s able to modify the invasive capability of prostate cancer cells, increasing the amount of shed vesicles and of their associated lytic enzymes.
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PMID:Osteoblast-conditioned media stimulate membrane vesicle shedding in prostate cancer cells. 1652 40

Hepatocyte growth factor (HGF) receptor Met and hypoxia-inducible factor-1 (HIF-1) signaling pathways are commonly activated in aggressive tumors and promote progression. Since both Met and HIF-1alpha proteins are heat shock protein (Hsp) 90 clients, Hsp90 inhibitors might be expected to positively impact tumor progression. Here, we systematically evaluated the inhibitory effects of the prototypical Hsp90 inhibitor geldanamycin (GA) on cellular processes involved in invasion and angiogenesis in T24 bladder cancer cells stimulated with HGF and chemical hypoxia. First, we demonstrated the positive feedback loop between Met and HIF-1 pathways, which serves to sustain and amplifies their signaling in T24 cells. GA downregulated Met by inhibiting new protein maturation, thereby dampening HGF signaling. HGF and chemical hypoxia with CoCl2 cooperatively promoted in vitro invasion and vascular endothelial growth factor (VEGF) secretion, while CoCl2 but not HGF activated urokinase-type plasminogen activator and matrix metalloproteinase 2, both of which promote invasion and angiogenesis. Low dose GA (100 nmol/L) inhibited these processes by suppressing both HGF and HIF-1 pathways. Notably, brief GA pretreatment inhibited in vitro invasion and VEGF secretion induced by HGF as effectively as did continuous treatment. Moreover, we found that GA inhibited activation of focal adhesion kinase, focal adhesion assembly, and actin reorganization induced by HGF and integrin engagement by extracellular matrix. Thus, GA widely suppresses extrinsic stimuli-induced signaling that contribute to tumor invasion and angiogenesis in this bladder carcinoma model, suggesting the utility of Hsp90 inhibitors in preventing tumor progression and metastasis.
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PMID:Low dose geldanamycin inhibits hepatocyte growth factor and hypoxia-stimulated invasion of cancer cells. 1752 27

The aim of this study was to investigate whether tumor cells as well as tumor-associated macrophages (TAMs) contribute to the generation of protease activities essential to tumor cell invasiveness, such as matrix metalloproteinase 2 and 9 (MMP-2 and MMP-9), and the urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR). We found that the enhanced invasiveness through Matrigel-coated filters of B16 murine melanoma cells stimulated with IFNgamma was associated with an higher expression of uPAR and MMP-9 in these cells. Moreover, treatment with anti-MMP-9 or anti-uPAR monoclonal antibodies abrogated the increase of invasiveness in IFNgamma-stimulated melanoma cells, suggesting a cooperation of uPA system and MMP-9 in cytokine-stimulated invasiveness. Invasiveness through Matrigel was also enhanced in B16 melanoma cells exposed to a medium conditioned by TAMs, represented in our experimental model by thioglycollate-elicited macrophages co-cultivated with melanoma cells. Macrophages isolated from these co-cultures were found to express higher levels of uPAR and MMP-9 compared to macrophage cultures alone, and the pro-invasive activity of the co-culture-conditioned medium was abrogated by anti-MMP-9 monoclonal antibodies, but not anti-uPAR monoclonal antibodies. Furthermore, the enhanced uPAR and MMP-9 expression in macrophages co-cultivated with tumor cells seems a rather specific phenomenon, generated through a cell-to-cell contact mechanism. On the whole, our data point to a cooperation between tumor cells and macrophages elicited by tumor cells themselves in generating key enzymes essential in the promotion of tumor invasiveness, such as uPAR and MMP-9.
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PMID:Tumoral and macrophage uPAR and MMP-9 contribute to the invasiveness of B16 murine melanoma cells. 1807 11

The scavenger receptor low-density lipoprotein receptor-related protein 1 (LRP-1) mediates the clearance of a variety of biological molecules from the pericellular environment, including proteinases which degrade the extracellular matrix in cancer progression. However, its accurate functions remain poorly explored and highly controversial. Here we show that LRP-1 silencing by RNA interference results in a drastic inhibition of cell invasion despite a strong stimulation of pericellular matrix metalloproteinase 2 and urokinase-type plasminogen activator proteolytic activities. Cell migration in both two and three dimensions is decreased by LRP-1 silencing. LRP-1-silenced carcinoma cells, which are characterized by major cytoskeleton rearrangements, display atypical overspread morphology with a lack of membrane extensions. LRP-1 silencing accelerates cell attachment, inhibits cell-substrate deadhesion, and induces the accumulation, at the cell periphery, of abundant talin-containing focal adhesion complexes deprived of FAK and paxillin. We conclude that in addition to its role in ligand binding and endocytosis, LRP-1 regulates cytoskeletal organization and adhesive complex turnover in malignant cells by modulating the focal complex composition, thereby promoting invasion.
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PMID:LRP-1 silencing prevents malignant cell invasion despite increased pericellular proteolytic activities. 1831 5

Upregulation of the PI3K pathway has often been reported in androgen-independent prostate cancer and is implicated in cancer cell survival and proliferation in the absence of androgen. Inhibition of PI3K by LY294002 suppressed cell invasion and motility of the highly metastatic androgen-independent Dunning rat prostate cancer MLL cell line with similar IC50 values and inhibition profile. Moreover, LY294002 attenuated expression of urokinase plasminogen activator (uPA) without any significant effect on that of matrix metalloproteinase 2. These results indicated that the role of PI3K in MLL cell invasion is by regulating cell motility and uPA expression.
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PMID:Suppression of prometastatic phenotype of highly metastatic androgen-independent rat prostate cancer MLL cell line by PI3K inhibitor LY294002. 1940 75

Matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator (uPA) are important factors for cancer invasion and metastasis, degrading the extracellular matrix. They are also associated with angiogenesis. Angiogenic phenotype is another feature of high-grade cervical intraepithelial neoplasia (CIN). However, their associations with the progression of low-grade CIN to high-grade CIN are unexplored. We investigated whether these proteolytic enzyme expressions correlate with the progression of CIN. A total of 39 paraffin-embedded specimens from 10 patients with CIN grade 1, nine with CIN grade 2, and 20 with CIN grade 3 were assessed immunohistochemically by specific antibodies against MMP-2, MMP-9, and uPA. MMP-9 expression was higher in CIN 3 lesions (47.4%) than in CIN 1 (22.2%) and CIN 2 (20.2%) lesions, although the difference failed to reach statistical significance. The expression level of uPA and MMP-2 was not associated with the grade of CIN lesions. Interestingly, we found a significant association between expressions of uPA and MMP-2 (P= 0.028). Our results suggest that MMP-9 might play a role in the progression of CIN.
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PMID:Expression of MMP-2, MMP-9, and urokinase-type plasminogen activator in cervical intraepithelial neoplasia. 1972 42

Hepatocyte growth factor (HGF) is a pleiotropic factor that plays multiple roles during mammalian development. We previously demonstrated that in the postnatal testes, the HGF receptor, c-met, is expressed by Leydig cells and HGF increases the steroidogenetic activity of the cells. In the present article, we report that HGF modifies the composition of the extracellular matrix of cultured Leydig cells. We show that HGF increases the metabolic activity of isolated Leydig cells; in particular, the factor increases urokinase plasminogen activator and matrix metalloproteinase 2 secretion. We have also shown that the levels of active transforming growth factor beta are increased by HGF. On the contrary, using the Western blotting technique, a strong reduction in the amount of fibronectin present in the culture medium of cells cultured in the presence of HGF has been detected. The presented data demonstrate that HGF modulates several functional activities of Leydig cells, further supporting the hypothesis that this factor has a relevant role in the regulation of mammalian spermatogenesis.
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PMID:Hepatocyte growth factor (HGF) modulates Leydig cell extracellular matrix components. 1983 31

CD146, an endothelial molecule involved in permeability and monocyte transmigration, has recently been reported to promote vessel growth. As CD146 is also detectable as a soluble form (sCD146), we hypothesized that sCD146 could stimulate angiogenesis. Experiments of Matrigel plugs in vivo showed that sCD146 displayed chemotactic activity on endogenous endothelial cells, and exogenously injected late endothelial progenitor cells (EPCs). Recruited endothelial cells participated in formation of vascular-like structures. In vitro, sCD146 enhanced angiogenic properties of EPCs, with an increased cell migration, proliferation, and capacity to establish capillary-like structures. Effects were additive with those of vascular endothelial growth factor (VEGF), and sCD146 enhanced VEGFR2 expression and VEGF secretion. Consistent with a proangiogenic role, gene expression profiling of sCD146-stimulated EPCs revealed an up-regulation of endothelial nitric oxide synthase, urokinase plasminogen activator, matrix metalloproteinase 2, and VEGFR2. Silencing membrane-bound CD146 inhibited responses. The potential therapeutic interest of sCD146 was tested in a model of hind limb ischemia. Local injections of sCD146 significantly reduced auto-amputation, tissue necrosis, fibrosis, inflammation, and increased blood flow. Together, these findings establish that sCD146 displays chemotactic and angiogenic properties and promotes efficient neovascularization in vivo. Recombinant human sCD146 might thus support novel strategies for therapeutic angiogenesis in ischemic diseases.
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PMID:Soluble CD146 displays angiogenic properties and promotes neovascularization in experimental hind-limb ischemia. 2018 88

Pathogenic bacteria, including Pseudomonas aeruginosa, interact with and engage the host plasminogen (Plg) activation system, which encompasses the urokinase (uPA)-type Plg activator, and is involved in extracellular proteolysis, including matrilysis and fibrinolysis. We hypothesized that secreted bacterial proteases might contribute to the activation of this major extracellular proteolytic system, thereby participating in bacterial dissemination. We report that LasB, a thermolysin-like metalloprotease secreted by Ps. aeruginosa, converts the human uPA zymogen into its active form (kcat=4.9 s-1, Km=8.9 microM). Accordingly, whereas the extracellular secretome from the LasB-expressing pseudomonal strain PAO1 efficiently activates pro-uPA, the secretome from the isogenic LasB-deficient strain PDO240 is markedly less potent in pro-uPA activation. Still, both secretomes induce some metalloprotease-independent activation of the human zymogen. The latter involves a serine protease, which we identified via both recombinant protein expression in Escherichia coli and purification from pseudomonal cultures as protease IV (PIV; kcat=0.73 s-1, Km=6.2 microM). In contrast, neither secretomes nor the pure proteases activate Plg. Along with this, LasB converts Plg into mini-Plg and angiostatin, whereas, as reported previously, it processes the uPA receptor, inactivates the plasminogen activator inhibitor 1, and activates pro-matrix metalloproteinase 2. PIV does not target these factors at all. To conclude, LasB and PIV, although belonging to different protease families and displaying quite different substrate specificities, both activate the urokinase-type precursor of the Plg activation cascade. Direct pro-uPA activation, as also reported for other bacterial proteases, might be a frequent phenomenon that contributes to bacterial virulence.
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PMID:Activation of human pro-urokinase by unrelated proteases secreted by Pseudomonas aeruginosa. 2033 95

Cancer metastasis is a major cause of death in cancer patients, with invasion as a first step greatly contributing to the failure of clinical treatments. Any compounds with an inhibitory influence on this process are therefore of prime interest. Momordica charantia (bitter melon) is widely consumed as a vegetable and especially as a folk medicine in Asia. Here, we investigated the anti-invasive effects of bitter melon leaf extract (BMLE) on a rat prostate cancer cell line (PLS10) in vitro and in vivo. The results indicated that non-toxic concentrations of BMLE significantly inhibited the migration and invasion of cells in vitro. The results of zymography showed that BMLE inhibited the secretion of MMP-2, MMP-9 and urokinase plasminogen activator (uPA) from PLS10. Real-time RT-PCR revealed that BMLE not only significantly decreased gene expression of MMP-2 and MMP-9, but also markedly increased the mRNA level of TIMP-2, known to have inhibitory effects on the activity of MMP-2. An EnzChek gelatinase/collagenase assay showed that collagenase type IV activity was partially inhibited by BMLE. In the in vivo study, intravenous inoculation of PLS10 to nude mice resulted in a 100% survival rate in the mice given a BMLE-diet as compared with 80% in the controls. The incidence of lung metastasis did not show any difference, but the percentage lung area occupied by metastatic lesions was slightly decreased in the 0.1% BMLE treatment group and significantly decreased with 1% BMLE treatment as compared with the control. Thus, the results indicate for the first time an anti-metastatic effect of BMLE both in vitro and in vivo.
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PMID:Momordica charantia leaf extract suppresses rat prostate cancer progression in vitro and in vivo. 2073 62


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