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)

Colon tumor cells are more responsive to certain growth modulators in their local environment in vivo than are normal colonocytes. Examples of this class of compounds are the fecal diglycerides (DGs)(E. Friedman et al., Cancer Res., 49: 544-548, 1989), which may act as endogenous tumor promoters. At the concentration found in vivo, fecal DGs composed of oleic, myristic, and palmitic fatty acids induced mitogenesis of all classes of benign tumor cells and of half of the resected carcinomas tested in primary culture, but induced no detectable mitogenesis of normal colonocytes. Colon tumor cells also exhibit selective responses to these endogenous modulators as measured by another biological parameter, secretion of urokinase from carcinomas than from normal colonocytes. Fecal DGs also induced a 13-fold increase in urokinase mRNA synthesis in colon carcinoma cells and induced secretion of active urokinase from each of five resected carcinomas. Colon carcinomas, at both the primary site and metastatic to the liver, secreted the Mr 55,000 form of urokinase constitutively and secreted the same form upon treatment with fecal DGs. An increase in the steady-state level of urokinase secretion by saturated-chain DGs exhibited a strong dependency on the chain length of the fatty acid residues, those of 14 and 16 carbons having the greatest activity. Thus, fecal DGs composed of oleic, myristic, and palmitic acid residues induce two biological activities selectively in colon tumor cells, each of which would enhance tumor development. Selective mitogenesis would increase adenoma and carcinoma cell number relative to normal colonocyte number, and induction of the proteolytic enzyme urokinase would aid local invasion of the carcinoma within the bowel wall.
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PMID:Urokinase secretion from human colon carcinomas induced by endogenous diglycerides. 210 72

CL26 murine colon carcinoma cells express urokinase-type plasminogen activator (u-PA) mRNA and activity after transfection with the activated c-Ha-ras-I (EJ-ras) oncogene cloned from the EJ bladder carcinoma. PA activity and mRNA in control cells transfected with the non-mutated c-Ha-ras-I (CO-ras) gene remained negative. Ras mRNA was detected in EJ-ras- and CO-ras-transfected cells, but not in untransfected or pSV2-neo-transfected cells. These results indicate that u-PA biosynthesis can be modulated by EJ-Ha-ras-dependent pathways of signal transduction.
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PMID:Urokinase-type plasminogen activator biosynthesis is induced by the EJ-Ha-ras oncogene in CL26 mouse colon carcinoma cells. 249 73

The regulation of urokinase secretion and receptor display in a well-differentiated colon carcinoma cell line, GEO, adapted to serum-free conditions was examined. In protein-free medium, the cell line secreted 0.8 +/- 0.1 ng/ml/10(6) cells of urokinase in a 3-day period as determined by an enzyme-linked immunosorbent assay. This value was elevated 4-fold when the cells were cultivated in the presence of epidermal growth factor (EGF) but not insulin or transferrin. Propagation of the cell line with any combination of these growth factors was not superior to EGF alone in inducing urokinase secretion. The presence of EGF raised the radioactive laminin-solubilizing activity of the conditioned medium. In the absence of the growth factor, spent medium supplemented with plasminogen solubilized 23,000 +/- 7,000 dpm/10(6) cells of the immobilized laminin. This value was increased to 95,000 +/- 10,000 dpm/10(6) cells when the cultures were grown with EGF. Northern analysis indicated that the elevated level of the plasminogen activator protein by EGF was a consequence of a more abundant urokinase transcript. The stimulation of urokinase secretion by EGF was accompanied by a reduction of radioactive urokinase binding to the cell line. The reduction in plasminogen activator binding was not further enhanced by insulin or transferrin. In addition, these latter growth factors, by themselves, were ineffective in altering the amount of plasminogen activator bound. The attenuation in 125I-labeled urokinase binding did not reflect occupation of the receptors with endogenous ligand as acid pretreatment was without effect on the binding profile. Scatchard analysis revealed that the altered urokinase binding by EGF reflected a decrease in receptor number from 14,000 +/- 1,500 to 8,000 +/- 1,500 sites per cell. The temporal relationship of urokinase secretion and receptor display was examined. Changes in either parameter required an EGF exposure period of 10 h or more. Further amplification of the EGF effects was seen with longer incubation times with the growth peptide. These opposite effects of EGF on urokinase secretion and receptor display may suggest a homeostatic control mechanism for keeping the plasminogen activator system in check. The ability of the cell line to express biological characteristics associated with a well-differentiated colon cell type may reflect its capacity to suppress a system which is usually associated with the transformed state.
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PMID:Determination of the effects of epidermal growth factor on urokinase secretion and urokinase receptor display in a well-differentiated human colon carcinoma cell line. 253 50

The expression of the plasminogen activator, urokinase, and the display of its receptor in response to growth factors were examined in a serum-free adapted colon cancer cell line, CBSsf. Cells propagated in protein-free medium secreted 6.5 +/- 1.0 ng/ml of urokinase/10(6) cells in a 3-day period as determined by enzyme-linked immunosorbent assay. Inclusion of insulin or transferrin into the protein-free medium was without effect on this parameter. However, addition of epidermal growth factor (EGF) to the protein-free medium resulted in a 50% reduction in this parameter. This change was also reflected in the plasminogen-dependent solubilization of immobilized radioactive laminin. Plasminogen-supplemented conditioned medium derived from CBSsf cells grown in protein-free medium solubilized 135,000 +/- 25,000 dpm/10(6) cells of radioactive substrate. This value was decreased to 59,000 +/- 6,000 when conditioned medium was collected in the presence of EGF. Dose-response curves indicated that, while 0.5 ng/ml of EGF were suboptimal for the suppression of urokinase secretion, a concentration of 5.0 ng/ml had a maximum effect on this measurement. Northern hybridization studies indicated that the reduced plasminogen activator reflected, at least in part, translation of a less abundant transcript. Examination of the colon carcinoma cell line for altered urokinase receptor display revealed that EGF caused a dose-dependent increase in the amount of radioactive urokinase bound. This did not reflect reduced occupation of binding sites with endogenous ligand. Scatchard manipulation of the binding data indicated that the increased amount of radioactive plasminogen activator bound to cells cultured with EGF reflected an increase in receptor number from 7,500 to 13,000 sites/cell. Time course studies revealed that the decrease in urokinase secretion precedes changes in receptor display by 5 h. A 60% reduction in assayable urokinase was demonstrated in the conditioned medium from cells treated with the growth peptide for 10 h. However, a 24-h period was required to observe an increase (80%) in the amount of radioligand bound to EGF-treated cells. These data suggest EGF to be a regulator of both urokinase production and urokinase receptor display in a colon cancer cell line.
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PMID:Examination of the effects of epidermal growth factor on the production of urokinase and the expression of the plasminogen activator receptor in a human colon cancer cell line. 253 3

At present, there is a lack of availability of differentiation markers for colon carcinoma. This may, in part, be a consequence of the diversified function of the normal human colon. This study addresses the possibility that the expression of urokinase and its receptor is inversely related to differentiation in colon carcinoma. Six colon carcinoma cell lines including three well-differentiated (CBS, GEO, FET) and three poorly differentiated ones (HCT116, HCT116b, RKO) were screened for urokinase receptor display and secretion of the plasminogen activator. A radioreceptor assay was used to determine receptor levels. Binding of radioactive urokinase to colon cells was saturable, specific, and time dependent. Cell-bound 125I-labeled protease was unaffected by the presence of epidermal growth factor, low-molecular-weight urokinase, plasminogen, or transferrin. Time course studies revealed that maximum amounts of radioactive tracer were bound in a 30-min period with no change occurring over the course of a 90-min incubation. Scatchard analysis of ligand binding indicated that the well-and poorly differentiated cells could be separated on the basis of receptor display; the aggressive RKO, HCT116, and HCT116b expressed in excess of 10(5) sites per cell, while the more indolent CBS, GEO, and FET possessed less than 1.5 X 10(4) receptors per cell. The colon carcinoma cells were also analyzed for urokinase in the conditioned medium. Low levels of the plasminogen activator (0.8 to 1.3 ng/ml/10(6) cells/72 h) were associated with the more "mature" cells. This was in contrast to the elevated levels of the protease (3.9 to 11.4 ng/ml/10(6) cells/72 h) present in the medium derived from the more aggressive cells (HCT 116, HCT116b, RKO). Thus, secreted urokinase and/or the expression of cellular receptor for the plasminogen activator may provide useful measurements of the degree of undifferentiation of in vitro colon carcinoma.
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PMID:Determination of the levels of urokinase and its receptor in human colon carcinoma cell lines. 283 52

The present study documents the effect of the planar, polar differentiation promoter N,N-dimethylformamide (DMF) on urokinase binding to colon carcinoma cells. Exposure of the colon carcinoma cell lines to the agent resulted in enhanced specific binding of radioactive urokinase to all cells tested. Insulin binding to the cells was, however, unaffected by DMF. A DMF exposure period of 45 h was required to observe maximum urokinase binding to two representative cell lines FET and RKO. Optimal stimulation of both cell lines occurred with 0.8% DMF. Scatchard analysis revealed the dissociation constants to be unchanged by the agent with the increased binding of radioactive plasminogen activator reflecting an up-regulation of binding sites. In this regard, the cell line RKO upon exposure to DMF, displayed approx. 700,000 receptors/cell, the highest value published, to date, for any cell line.
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PMID:Modulation of the urokinase receptor in human colon cell lines by N,N-dimethylformamide. 283 92

This study documents the ability of substrata material derived from well but not poorly differentiated colon carcinoma cells to alter the biological characteristics of a separate colon carcinoma cell line (MOSERSF). To assess changes induced by the presence of these substrata, MOSERSF cells were screened for (a) morphological features, (b) secretion of carcinoembryonic antigen (CEA), (c) alteration of urokinase levels, and (d) sensitivity to the growth-inhibitory peptide transforming growth factor beta. Morphologically, MOSERSF cells grown on plastic displayed a rounded shape and could be detached by agitation. Subculturing of these cells onto substrata laid down by well differentiated (mature) colon carcinoma cells resulted in cell attachment and spreading. These changes did not manifest themselves when cells were plated on material derived from poorly differentiated (primitive) colon cells. Conditioned medium from MOSERSF cells grown on plastic or on colon-derived material from the well and poorly differentiated colon cells were compared for CEA levels. Substrata derived from undifferentiated cells were without effect on assayable CEA (substrata absent, 1.4 ng/ml/10(6) cells/72 h; substrata present, 1.4-1.7 ng/ml/10(6) cells/72 h). However, growth of MOSERSF cells on material deposited by well differentiated colon cells resulted in a 3-fold increase in the level of CEA. Spent medium was also analyzed for urokinase. A high level of the protease (20.3 ng/ml/10(6) cells/72 h) was expressed by MOSERSF cells. The concentration of the enzyme was reduced by over 50% when MOSERSF cells were propagated on substrata laid down by well differentiated cells. An enhanced sensitivity to the growth-retarding effects of transforming growth factor beta was seen with certain substrata. On plastic, transforming growth factor beta inhibited proliferation of MOSERSF cells with a median effective concentration of 0.65 ng/ml. However, on substrata from mature but not primitive cells, MOSERSF cells exhibited an increased sensitivity to the peptide (median effective concentration, 0.16 ng/ml). Colon-derived material obtained from both well differentiated and poorly differentiated colon carcinoma cells was compared after [35S]-methionine metabolic labeling. More [35S]methionine was incorporated into the material from the "mature" colon cells. The substrata could also be distinguished by quantitative differences in a number of high molecular weight proteins. Immunofluorescence of colon-deposited material revealed the presence of laminin and fibronectin.
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PMID:Alterations of the biological characteristics of a colon carcinoma cell line by colon-derived substrata material. 316 26

It was previously demonstrated that substrata derived from well differentiated colon carcinoma cell lines induced a more benign program in a separate malignant colon cell line, MOSERsf. This study attempts to define a role for extracellular matrix components in the biological events of MOSERsf cells. Alterations in morphology, secreted carcinoembryonic antigen (CEA) and urokinase brought about by individual components were determined. Laminin induced similar changes to colon-derived substrata in that there was increased cell attachment and spreading, a 4-fold elevation in CEA and a 45% reduction in urokinase. Fibronectin stimulated cell attachment without altered morphology and reduced the amount of plasminogen activator. CEA values, however, remained unchanged. Growth of MOSERsf cells on all types of collagen failed to elicit any change in cell shape or CEA. However, type I/III collagen raised urokinase levels by 40%. Transforming growth factor beta (TGF-beta) induces cellular laminin and fibronectin, promotes cell attachment, and spreading, elevates CEA and diminishes urokinase. These data argue for a role for laminin and possibly fibronectin in the governing of biological events culminating in a more mature colon cell.
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PMID:Alteration in the behavior of a colon carcinoma cell line by extracellular matrix components. 316 44

Colon carcinoma cells are first found as microscopic foci within benign tumors or adenomas. The carcinoma must invade the adenoma which protrudes into the colon lumen before it can infiltrate the bowel wall. A quantitative model for this process has been developed in tissue culture in which human colon carcinoma cells destroy cocultivated adenoma colonies. 43 adenoma colonies were assayed by cocultivation with carcinoma cells. Constitutive secretion of the urokinase form of plasminogen activator by carcinoma cells apparently plays some role in adenoma destruction as inhibition of this protease by the competitive inhibitor benzamidine reversibly inhibited adenoma destruction (p less than 0.01). Elevation of plasminogen activator secretion by addition of the tumor promoter 12-tetradecanoylphorbol-13-acetate significantly enhanced the destruction of colonies cultured from tubular adenomas with only mild dysplasia (p less than 0.025) and from villous, villotubular and tubular adenomas with moderate to severe dysplasia (p less than 0.0005).
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PMID:Tumor-promoter-enhanced destruction of noninvasive human benign colon tumor cells by cocultivated carcinoma cells. 323 26

nm23H1 has properties of a metastasis suppressor gene. Although its mechanism of action is unknown, nm23 has been implicated in transforming growth factor beta 1 (TGF beta 1) signal transduction. In an earlier study we decreased nm23 mRNA levels 2- to 8-fold by antisense phosphorothiolated oligonucleotides in two HT29 colon carcinoma sublines at different stages in tumor progression with different responses to TGF beta 1: the HD3 subline, which shows TGF beta 1-induced growth arrest and differentiation; and the more tumorigenic U9 subline, whose growth and invasion are stimulated by TGF beta 1. Only TGF beta 1-mediated responses in HD3 cells were inhibited by nm23 antisense oligos, suggesting that nm23 functions in only one TGF beta 1 signaling pathway. In the current report we have extended this study to cell motility. HD3 motility was increased by nm23 phosphorothiolated antisense oligos which decrease nm23 mRNA levels, while HD3 cell motility was conversely decreased by TGF beta 1 which increases nm23 mRNA levels. HD3 motility was not increased by basic FGF, TGF beta 1 or TGF alpha, while the 13-fold higher basal motility of U9 cells was stimulated 3-fold by basic FGF, 4-fold by TGF beta 1 and 5-fold by TGF alpha, but not by scatter factor. Differences in motility and response to motility factors could not be ascribed to differences in either basal levels of proteases or modulation of their levels by TGF beta 1. Both HD3 and U9 cells displayed equal levels of urokinase activity and mRNA, equal expression of the metalloproteinase inhibitor TIMP-1, and no detectable collagenases by zymography. No differential response to TGF beta 1 was seen in any of these assays. Thus limited cell motility and lack of response to motility factors in HD3 colon cancer cells could be correlated with expression of nm23 active in signal transduction.
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PMID:Colon carcinoma cells with inactive nm23 show increased motility and response to motility factors. 755 87


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