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)

We have identified a leukemia-differentiating activity (LDA) in medium conditioned by the LD-1 melanoma, a G-CSF secreting human tumor line. Partially-purified LDA induces HL-60 cells to produce superoxide, become phagocytic, and to develop macrophage-like morphology and surface markers. The LDA markedly suppresses clonal growth in agar of HL-60 cells, and cells of the human myeloid leukemia lines PBL 985 and K562, but does not suppress clonal growth of the B-lymphoblast lines Raji and Daudi. The molecular weight of this material is approx. 40,000 daltons. It can be separated from the bulk of the colony stimulating activity on phenyl sepharose chromatography. The LDA is not neutralized by antibodies to G-CSF, GM-CSF, IFN alpha, IFN gamma, TNF, urokinase, and tissue plasminogen activator, and is not inhibited by preincubation with aprotinin. The LDA in conditioned medium may be different from previously described differentiating factors, and may represent an additional class of human growth regulators.
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PMID:Leukemia-differentiating activity expressed by the human melanoma cell line LD-1. 316 98

The importance of cell-associated plasminogen activation in tumor invasion and metastasis is becoming increasingly evident. To clarify the modulators of cell-associated plasminogen activation in malignant states, we have recently established an assay system utilizing endogenous plasminogen activators on the cell surface. In the present study using the assay system, we found that the conditioned medium from phorbol 12-myristate 13-acetate (PMA)-stimulated human lymphoid cell lines, HUT 78 and Raji, strongly enhanced plasminogen activator (PA) activity on the surface of human malignant tumor cell lines (WI-38 VAI3 2RA, A431, A549 and HT-1080). The enhancing effect was inhibited by the addition of actinomycin D. By gel filtration, the active substances in PMA-stimulated HUT 78- and Raji-conditioned media were eluted in similar fractions corresponding to molecular weights of 60 to 80 kDa. The active substance was heat-labile. The enhanced PA activities were completely inhibited by anti-urokinase-type plasminogen activator (uPA) IgG. Moreover, the active substance was found to increase in cell-bound uPA antigen. These findings suggest that a population of activated lymphocytes produces a plasminogen activator modulator that induces uPA on the surface of malignant tumor cells.
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PMID:Phorbol-ester-stimulated human lymphoid cell lines produce a plasminogen activator modulator inducing cell-bound urokinase-type plasminogen activator in malignant tumor cell lines. 856 14

Human lymphoproliferative diseases can be hypothesized to invade locally and to metastatize via mechanisms similar to those developed by a variety of solid tumors, i.e., the secretion of extracellular matrix-degrading enzymes and stimulation of angiogenesis. To assess this hypothesis, Namalwa, Raji, and Daudi cell lines (Burkitt's lymphoma), LIK and SB cell lines (B-cell lymphoblastic leukemia), CEM and Jurkat cell lines (T-cell lymphoblastic leukemia), and U266 cell line (multiple myeloma) were evaluated for their capacity to produce matrix metalloproteinase-2 and -9, and urokinase-type plasminogen activator. These cell lines were also assessed for their ability: (1) to produce the angiogenic basic fibroblast growth factor and vascular endothelial growth factor; (2) to induce an angiogenic phenotype in cultured endothelial cells, represented by cell proliferation, chemotaxis, and morphogenesis; (3) to stimulate angiogenesis in different in vivo experimental models. All cell lines expressed the mRNA for one or both metalloproteinases. Namalwa, Raji, LIK, SB, and U266 cells secreted the active form of both metalloproteinases, while Daudi, CEM, and Jurkat cells produced metalloproteinase-2 but not-9. In contrast, urokinase-type plasminogen activator was secreted only by SB cells. While Raji, LIK, SB, CEM, and Jurkat cells secreted both basic fibroblast growth factor and vascular endothelial growth factor, Daudi and U266 cells produced only the former, and Namalwa cells only the latter. Accordingly, the conditioned medium of all cell lines stimulated cell proliferation and/or chemotaxis in cultured endothelial cells, with the exception of that of Namalwa cells which was ineffective. The conditioned medium of CEM and Jurkat cells induced morphogenesis in cultured endothelial cells grown on a reconstituted basement membrane (Matrigel). Lastly, Namalwa, Raji, LIK, SB, U266, CEM, and Jurkat cells induced angiogenesis and mononuclear cell recruitment in the murine Matrigel sponge model and in a chick embryo chorioallantoic membrane assay. The extent of angiogenesis in both models was strictly correlated with the density of the mononuclear cell infiltrate. The results indicate that human lymphoproliferative disease cells possess both local and remote invasive ability via the secretion of matrix-degrading enzymes and the induction of angiogenesis which is fostered by host inflammatory cells and by an intervening ensemble of angiogenic factors.
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PMID:Human lymphoblastoid cells produce extracellular matrix-degrading enzymes and induce endothelial cell proliferation, migration, morphogenesis, and angiogenesis. 959 64

Ovarian cancer metastasis is associated with an increase in the urokinase-type plasminogen activator (uPA) and its receptor uPAR. We present evidence that binding of uPA to uPAR provokes a mitogenic response in the human ovarian cancer cell line OV-MZ-6 in which endogenous uPA production had been significantly reduced by stable uPA 'antisense' transfection. High molecular weight (HMW) uPA, independent of its enzymatic activity, produced an up to 95% increase in cell number concomitant with 2-fold elevated [3H]thymidine incorporation as did the catalytically inactive but uPAR binding amino-terminal fragment of uPA, ATF. uPA-induced cell proliferation was significantly decreased by blocking uPA/uPAR interaction by the monoclonal antibody IIIF10 and by soluble uPAR. The efficiency of the uPAR binding synthetic peptide cyclo19,31 uPA19-31 to enhance OV-MZ-6 cell growth proved this molecular domain to be the minimal structural determinant for uPA mitogenic activity. Dependence of uPA-provoked cell proliferation on uPAR was further demonstrated in Raji cells which do not express uPAR and were thus not induced by uPA. However, upon transfection with full-length uPAR, Raji cells acquired a significant growth response to HMW uPA and ATF.
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PMID:Urokinase induces proliferation of human ovarian cancer cells: characterization of structural elements required for growth factor function. 982 67

HL-60, a cell line originating from a human myeloid leukemia, expresses urokinase-type plasminogen activator (uPA) on the mRNA level and secretes the protein into the culture supernatant. Additionally, uPA receptors (uPA-R) could be detected in HL-60 on both the mRNA and the protein level, whereas the lymphoblastic cell line Raji studied in parallel was uPA-R negative. The cell lines were further studied in their clonal growth in methylcellulose under the influence of rhuPA (rhpro-uPA). The growth of Raji cells was not influenced by rhuPA. Colony and cluster formation of HL-60 was not reproducibly affected by rhuPA in concentrations between 1-100 ng/ml. In some experiments however, there were higher numbers of colonies in the HL-60 cultures incubated with rhuPA which was due to a cluster-to-colony shift. Furthermore, the HL-60 colonies in the rhuPA incubated plates always showed morphological alterations including an adherent basis indicating functional differentiation. This assumption was further supported by the observation that the secondary plating efficiency (PE2) of HL-60 cells taken from single colonies of uPA-incubated plates decreased significantly when compared with PE2 of cells from colonies grown without the presence of uPA. In conclusion, the intact uPA molecule functions like an autocrine cytokine for a human leukemic cell line, which in addition to its effects in tumor invasion makes it an interesting target molecule for further studies on tumor suppression.
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PMID:Urokinase-type plasminogen-activator (upa), a protease with cytokine-like activity in human hl-60 leukemic-cell line. 2157 7

In this work, the benzimidazole-pyrrole conjugates 6a-h and benzimidazole-tetracycles conjugates 12-14 were prepared. The cytotoxicity of the compounds 3, 4a-h, 6a-h, 8, 10 and 12-14 was tested against lung cancer cell line A549. Compound 6b exhibited higher activity than the bis-benzoxazole natural product (UK-1), the standard. The tested 4g,h, 6a-h, 10 and 12-14 exhibited remarkable cytotoxicity activity against breast cancer cell line MCF-7 with higher activity than tamoxifen. Furthermore, compound 4h was found to be also more potent than doxurubicin. The antitumor promotion activity of synthesized compounds 4g,h, 6a-h, 10 and 12-14 has been estimated by studying their possible inhibitory effects on EBV-EA activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the studied compounds, the inhibitory activities of compounds 8, 13 and 14 demonstrated strong inhibitory effects on the Epstein-Barr virus early antigen (EBV-EA) activation without showing any cytotoxicity on the Raji cells and their effects being stronger than that of a representative control, oleanolic acid. Moreover, the molecular docking of the new compounds into plasminogen activator (uPA) receptor has been in correlation with the antitumor activity. All synthesized compounds 3, 4a-h, 6a-h, 8, 10 and 12-14 were docked into same groove of the binding site of the native co-crystalized (4-iodobenzo[b]thiophene-2-carboxamidine) ligand (PDB code:1c5x) for activity explaination. Compounds 4h, 6b and 13, giving the best docking results, were further studied to estimate their effect on the level of uPA using AssayMax human urokinase (uPA) ELISA kit. In case of A549 cell line, compound 6 exhibited similar activity to MMC, and for MCF-7 cell line, compound 4h exhibited similar activity to doxorubicin, in inhibiting the expression of uPA.
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PMID:Synthesis and docking studies of novel antitumor benzimidazoles. 2312 17