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)

The migration of endothelial cells in response to various stimulating factors plays an essential role in angiogenesis. The p38 MAPK pathway has been implicated to play an important role in endothelial cell migration because inhibiting p38 MAPK activity down-regulates vascular endothelial growth factor (VEGF)-stimulated migration. Currently, the signaling components in the p38 MAPK activation pathway and especially the mechanisms responsible for p38 MAPK-regulated endothelial cell migration are not well understood. In the present study, we found that p38 MAPK activity is required for endothelial cell migration stimulated by both VEGF and nongrowth factor stimulants, sphingosine 1-phosphate and soluble vascular cell adhesion molecule. By using dominant negative forms of signaling components in the p38 MAPK pathway, we identified that a regulatory pathway consisting of MKK3-p38alpha/gamma-MAPK-activated protein kinase 2 participated in VEGF-stimulated migration. In further studies, we showed that a minimum of a 10-h treatment with SB203580 (specific p38 MAPK inhibitor) was needed to block VEGF-stimulated migration, suggesting an indirect role of p38 MAPK in this cellular event. Most interestingly, the occurrence of SB203580-induced migratory inhibition coincided with a reduction of urokinase plasminogen activator (uPA) expression. Furthermore, agents disrupting uPA and uPA receptor interaction abrogated VEGF-stimulated cell migration. These results suggest a possible association between cell migration and uPA expression. Indeed, VEGF-stimulated migration was not compromised by SB203580 in endothelial cells expressing the uPA transgene; however, VEGF-stimulated migration was inhibited by agents disrupting uPA-uPA receptor interaction. These results thus suggest that the p38 MAPK pathway participates in endothelial cell migration by regulating uPA expression.
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PMID:p38 Mitogen-activated protein kinase regulation of endothelial cell migration depends on urokinase plasminogen activator expression. 1537 54

Three decades of research have revealed that cancer is easier to prevent than to treat and that consumption of certain fruits and vegetables can reduce the risk of cancer. Whereas chemotherapy is designed to destroy cancer after it appears, chemoprevention involves the abrogation or delay in the onset of cancer. Regardless of whether a chemopreventive or chemotherapeutic approach is taken, cancer is a multifactorial disease that requires modulation of multiple pathways and multiple targets. Various molecular targets of chemoprevention are also relevant to the therapy of cancer. These targets include the activation of apoptosis; suppression of growth factor expression or signalling; downregulation of antiapoptotic proteins; suppression of phosphatidylinositol-3'-kinase/Akt, NF-kappaB, Janus kinase-signal transducer and activator of transcription and activator protein-1 signalling pathways; and downregulation of angiogenesis through inhibition of vascular endothelial growth factor expression, cyclooxygenase-2, matrix metalloproteinase-9, urokinase-type plasminogen activator, adhesion molecules and cyclin D1. Pharmacologically safe phytochemicals that have been identified from plants or their variant forms can modulate these molecular targets. These phytochemicals include genistein, resveratrol, dially sulfide, S-ally cysteine, allicin, lycopene, capsaicin, curcumin, 6-gingerol, ellagic acid, ursolic acid, betulinic acid, flavopiridol, silymarin, anethol, catechins and eugenol. Recent work has shown that these phytochemicals also can reverse chemoresistance and radioresistance. Because of their pharmacological safety, these agents can be used alone to prevent cancer and in combination with chemotherapy to treat cancer.
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PMID:From chemoprevention to chemotherapy: common targets and common goals. 1546 61

Tumor angiogenesis is influenced by a large number of angiogenic factors among which vascular endothelial growth factor (VEGF) is one of the most important cytokines. Together with hepatocyte growth factor/scatter factor (HGF/SF), c-Met receptor forms a paracrine signaling system. The aim was to study the characterization of the proteins, VEGF, c-Met and HGF/SF with expression pattern and possible co-expression in secondary pleural tumors. Biopsy specimens of the pleural region from 70 patients were chosen and analyzed using immunohistochemistry and in situ hybridization. In the investigated tumors, a marked intracytoplasmic expression, sometimes over-expression of VEGF, c-Met and HGF/SF was detected. This expression was not connected to certain tumor types or a certain histogenetic origin of the tumor. These results indicate a role of these factors in angiogenesis. The synthesis of VEGF and c-Met within the tumor cells was established by in situ hybridization. There was a significant co-expression of VEGF and c-Met/HGF. Thus, autocrine stimulation of these angio-genetically effective systems may be present here. Importantly, the autocrine mechanism between over-expressed c-Met and HGF/SF in malignant tumors, already preferred by other authors, with demonstration of the proteins in the same tumor cells, has to be assumed in the process of pleural metastatic spread. Simultaneous synthesis of these three different proteins is also possible via the plasminogen-urokinase system. VEGF is reported to increase vascular permeability, which in turn causes pleural effusions. The results presented here may be the basis for possible future palliative therapeutical strategies in malignant pleural effusions.
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PMID:Co-expression of VEGF, c-Met and HGF/SF in secondary pleural tumors. 1549 46

AML patients may suffer from a disseminated coagulopathy, which can aggravate a pre-existing bleeding tendency due to thrombocytopenia and platelet dysfunction. The cellular and molecular mechanisms underlying this coagulopathy, however, are not completely understood. Indeed, the broad and increasing therapeutic use of cytotoxic drugs and growth factors is likely to contribute to the complexity of hemostatic abnormalities encountered in this hematologic malignancy. The nature of coagulation activation in AML was therefore investigated in vitro using the human leukemic cell line, HL60. Tissue factor (TF) was almost entirely located on the cell surface and bound factor VIIa, but only 15-25% of this TF was primarily functionally active. Treatment with increasing concentrations of daunorubicin or cytosine-beta-D-arabinofuranoside, two cytotoxic drugs commonly used in AML therapy, induced apoptosis and secondary necrosis of HL60 cells and resulted in marked decryption of TF PCA independent of de novo protein synthesis. This PCA-modulating effect was concomitant with and functionally dependent on the exposure of phosphatidylserine on the outer membrane leaflet. Similar observations were made in analogous ex vivo studies on patient-derived myeloblasts. Incubation of HL60 cells with GM-CSF, a cytokine expressed in the bone marrow microenvironment and used as an adjunct to AML treatment, evoked a cellular response, which included both enhanced TF production and release of VEGF-A and uPA into the culture medium. We conclude that both decryption of pre-formed TF PCA by chemotherapeutic drugs and de novo induction of TF by cytokines such as GM-CSF can regulate the pro-coagulant phenotype of HL60 cells in vitro.
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PMID:An in vitro study on the mechanisms of coagulation activation in acute myelogenous leukemia (AML): role of tissue factor regulation by cytotoxic drugs and GM-CSF. 1554 44

We earlier demonstrated that oral infusion of green tea polyphenols inhibits development and progression of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Evidence indicates that elevated levels of IGF-I with concomitant lowering of IGF binding protein (IGFBP)-3 are associated with increased risk for prostate cancer development and progression. In this study, we examined the role of IGF/IGFBP-3 signaling and its downstream and other associated events during chemoprevention of prostate cancer by green tea polyphenols in TRAMP mice. Our data demonstrated an increase in the levels of IGF-I, phosphatidylinositol 3'-kinase, phosphorylated Akt (Thr-308), and extracellular signal-regulated kinase 1/2 with concomitant decrease in IGFBP-3 in dorso-lateral prostate of TRAMP mice during the course of cancer progression, i.e., as a function of age. Continuous green tea polyphenol infusion for 24 weeks to these mice resulted in substantial reduction in the levels of IGF-I and significant increase in the levels of IGFBP-3 in the dorso-lateral prostate. This modulation of IGF/IGFBP-3 was found to be associated with an inhibition of protein expression of phosphatidylinositol 3'-kinase, phosphorylated forms of Akt (Thr-308) and extracellular signal-regulated kinase 1/2. Furthermore, green tea polyphenol infusion resulted in marked inhibition of markers of angiogenesis and metastasis most notably vascular endothelial growth factor, urokinase plasminogen activator, and matrix metalloproteinases 2 and 9. Based on our data, we suggest that IGF-I/IGFBP-3 signaling pathway is a prime pathway for green tea polyphenol-mediated inhibition of prostate cancer that limits the progression of cancer through inhibition of angiogenesis and metastasis.
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PMID:Oral consumption of green tea polyphenols inhibits insulin-like growth factor-I-induced signaling in an autochthonous mouse model of prostate cancer. 1557 82

The vascular endothelial growth factor (VEGF) and the plasminogen activator system play an essential role in solid tumor angiogenesis and in tumor invasion and metastasis. In the present study we investigated the relationship between patient outcome and levels of VEGF, urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in tumor cytosols of 196 node-negative primary invasive breast cancer patients who did not receive any adjuvant therapy. The median follow-up was 65 months. VEGF, uPA and PAI-1 were measured by commercially available enzyme-linked immunosorbent assays. Cox's univariate analysis showed that pT (p = 0.0007), uPA (p = 0.0156) and PAI-1 (p = 0.0015) had a significant impact on relapse-free survival, whereas VEGF did not have any prognostic value (p = 0.18). Bivariate analysis showed significant interactions between uPA and PAI-1 (p = 0.0035) and between VEGF and PAI-1 (p = 0.006). Our study confirms that uPA and PAI-1 cytosol levels can be considered as prognostic factors for relapse-free survival in node-negative breast cancer. Moreover, the interaction between VEGF and PAI-1 warrants further investigation into the relationship between the biomarkers of angiogenesis and those of the protease cascade.
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PMID:The prognostic value of vascular endothelial growth factor, urokinase plasminogen activator and plasminogen activator inhibitor-1 in node-negative breast cancer. 1564 34

Sp1 is a transcription factor for many genes, including genes involved in tumorigenesis. We found that human fibroblast cells malignantly transformed in culture by a carcinogen or by stable transfection of an oncogene express Sp1 at 8-fold to 18-fold higher levels than their parental cells. These cell lines form fibrosarcomas in athymic mice with a very short latency, and the cells from the tumors express the same high levels of Sp1. Similar high levels of Sp1 were found in the patient-derived fibrosarcoma cell lines tested, and in the tumors formed in athymic mice by these cell lines. To investigate the role of overexpression of Sp1 in malignant transformation of human fibroblasts, we transfected an Sp1 U1snRNA/Ribozyme into two human cell lines, malignantly transformed in culture by a carcinogen or overexpression of an oncogene, and into a patient-derived fibrosarcoma cell line. The level of expression of Sp1 in these transfected cell lines was reduced to near normal. The cells regained the spindle-shaped morphology and exhibited increased apoptosis and decreased expression of several genes linked to cancer, i.e., epithelial growth factor receptor, urokinase plasminogen activator, urokinase plasminogen activator receptor, and vascular endothelial growth factor. When injected into athymic mice, these cell lines with near normal levels of Sp1 failed to form tumors or did so only at a greatly reduced frequency and with a much longer latency. These data indicate that overexpression of Sp1 plays a causal role in malignant transformation of human fibroblasts and suggest that for cancers in which it is overexpressed, Sp1 constitutes a target for therapy.
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PMID:Down-regulation of overexpressed sp1 protein in human fibrosarcoma cell lines inhibits tumor formation. 1570 2

We have established the well-defined cycling, pseudo-pregnant and pregnant rhesus monkey models, and used these to analyze expression of the common molecules specifically related to angiogenesis, apoptosis or proteolysis, such as vascular endothelial growth factor (VEGF) and its receptors KDR, flt-1, flt-4 and flk-1, basic fibroblast growth factor (bFGF) and its receptors Flg, transforming growth factor-alpha and beta1 (TGF-a/beta1), and TGF-beta1 receptor type I (TbetaR-I) and type II (TbetaR-II), as well as steroidogenic acute regulatory protein (StAR), tissue type plasminogen activator/urokinase plasminogen activator/plasminogen activator inhibitor type 1 (tPA/uPA/PAI-1) and matrix matalloproteinase type 1, -3/tissue inhibitor matalloproteinase type 1, -2, -3 (MMP-1, -3/TIMP-1, -2, -3), Fas/FasL, BcL-2/Bax, in the corpus luteum (CL), in the functional layer of the endometrium and in the materno-fetal boundary of the implantation site. We have demonstrated that: expression of these molecules in the monkey CL, endometrium and materno-fetal boundary of the implantation site is correlated well with CL functional and vascular development and with the processes involved in the establishment of the implantation window as well as with the early stages of placentation. A coordinated increase in tPA and its inhibitor PAI-1 expression in the monkey and rat CL may be instrumental in initiating luteal regression in both species, and correlated well with the timing of the closure of the implantation window, whereas high uPA activity in the CL is important for the early formation of the CL and for maintaining its function which is closely correlated to the period of establishment of the implantation window. Apoptosis, proteolysis and angiogenesis occur in the CL and in the endometrium during the time of establishment of the implantation window, as well as in the materno-fetal boundary of the implantation site at the early stages of placentation. It seems that these processes occur in these tissues in a coordinated and time- and cell-dependent manner, and are reliant on each other. Based on these observations, we have designed experiments to test the actions of some related available compounds on mouse implantation, used alone or in combination. The preliminary data showed that the compounds which could effectively affect apoptosis, angiogenesis or proteolysis in the implantation site were capable of effectively inhibiting implantation by acting on the endometrium and/or on the CL. Furthermore, the combined use of these compounds produced an obvious additive effect on inhibiting implantation. This finding suggested this may be a good approach for developing an anti-implantation agent.
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PMID:Involvement of molecules related to angiogenesis, proteolysis and apoptosis in implantation in rhesus monkey and mouse. 1579 44

The aim of this study was to investigate the relationship of Interleukin-8 (IL-8) with vascular endothelial growth factor (VEGF) and plasminogen activator system (PA system) in the progression of colorectal cancer (CRC). In eighty-seven patients with CRC, the levels of IL-8, and VEGF as representative angiogenic factors and urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), and PAI-2 as representative invasive factors were quantitatively assayed in tumor and adjacent normal tissues. The levels of IL-8, VEGF, and PA system factors in tumor tissues were all significantly higher than those in normal tissues. The IL-8 level was significantly associated with tumor size, depth of infiltration, Dukes stage, and liver metastasis, and also significantly correlated with the levels of VEGF, uPAR, uPA, and PAI-1. The VEGF level was significantly associated with tumor size, vascular involvement. The levels of uPAR and PAI-1 were significantly associated with tumor size and depth of infiltration, and the uPAR level was associated with liver metastasis. The VEGF level was significantly correlated with the levels of uPAR and PAI-1. These results reveal that IL-8, VEGF, and PA system factors are contributed to tumor growth, invasion, and metastasis in CRC. Univariate analysis revealed that high levels of IL-8, VEGF, and uPAR were significantly associated with a shorter overall survival time; however, multivariate analysis identified only liver metastasis as an independent prognostic factor. In conclusion, IL-8 is responsible to tumor progression and liver metastasis of CRC, and the activation of PAS induced by IL-8 as well as VEGF may play an important role in the progression of CRC.
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PMID:Association of interleukin-8 and plasminogen activator system in the progression of colorectal cancer. 1608 82

Multiple myeloma (MM), a B-cell malignancy characterized by proliferation of monoclonal plasma cells remains incurable. Murine plasma cell tumors share common features with human MM. We used two cell lines (B38 and C11C1) derived from P3X63Ag8 myeloma cells. The new cell lines were implanted subcutaneously in the strain of origin (Balb/c mice) and used as a model to monitor the effects of C11C1 monoclonal antibody (mAb) to kininogen (HK). We assessed their behavior by intraperitoneal and subcutaneous implantation, by implanting them together and by treating B38-MM with purified mAb C11C1. We evaluated growth, microvascular density (MVD), and cellular expression of urokinase-type plasminogen activator-receptor (uPAR), fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), bradykinin-1 receptor (B1R), bradykinin-2 receptor (B2R) and HK. We found that both MM-cell-lines are uPAR positive, that mAb C11C1 inhibits its own tumor growth in vivo, slows down B38-MM growth rate when both MM are implanted together and when mAb C11C1 is injected intraperitoneally. MAb C11C1-treated-MM showed decreased MVD and HK binding in vivo without FGF-2, B1R or B2R expression changes. We propose that the B38-extramedullary-myeloma-model is a useful tool to study the interactions of this hematopoietic tumor and its environment and that mAb C11C1 may improve the efficacy of conventional MM treatment with minimal side effects.
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PMID:Multiple myeloma in a murine syngeneic model:modulation of growth and angiogenesis by a monoclonal antibody to kininogen. 1618 87


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