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)

It is the ability to invade and metastasize that ultimately determines the prognosis in cancer. Comprising one of the key groups of molecules involved in invasion and metastasis are proteases such as urokinase plasminogen activator and cathepsins B, D, and L, as well as various metalloproteases. These proteases catalyze degradation of the interstitial matrix and basement membranes, allowing cancer cells to invade locally and metastasize to distant sites. If proteases are directly and causally involved in cancer spread, they have the potential to be new prognostic markers in cancer. One of the best examples of a correlation between high levels of a protease in a primary tumor and poor prognosis is urokinase plasminogen activation in breast cancer. In this malignancy, the urokinase plasminogen activator is a strong and independent prognostic marker and may be a marker for axillary node-negative disease. The urokinase plasminogen activator may also be a prognostic marker in other cancers such as gastric, colorectal, lung, bladder, cervical, and ovarian cancers. In a number of studies, cathepsin D has been shown to be a prognostic factor in breast cancer. However, results with cathepsin D, especially when immunocytochemistry is used for its detection, are conflicting. Levels of cathepsin B, cathepsin L, and certain metalloproteases may also supply prognostic data in certain cancers, but results with these proteases are still preliminary.
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PMID:Proteases as prognostic markers in cancer. 981 10

Ras activates a multitude of downstream activities with roles in cellular proliferation, invasion and metastasis, differentiation, and programmed cell death. In this work we have evaluated the requirement of extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal kinase kinase (JNKK), and c-Jun/AP-1 activities in transformation and extracellular matrix invasion of ras oncogene expressing NIH 3T3 fibroblasts by expressing stable mutant genes that constitutively inhibit these activities. Whereas the inhibition of ERK activity reverts the transformed and invasive phenotype, the inhibition of the JNK pathway and AP-1 trans-activating activities by JNKK[K129R] and c-Jun(TAM67) had no effect on the ability of the ras oncogene-expressing cells to grow in soft agar or invade Matrigel basement membrane. Thus an elevated JNK activity and/or c-Jun/AP-1 trans-activating activity are not absolute requirements for ras transformation or invasion through basement membrane, and the dependence on AP-1 activity for transformation is cell-specific. However, inhibition of JNK kinase (JNKK) in ras-transformed cells with normally elevated JNK activity switches the protease-dependent invasive phenotype from a urokinase plasminogen activator (uPA)-dependent to a cathepsin L (CL)-dependent invasive phenotype. Conversely, treatment of ras-transformed cells of low constitutive JNK activity with the JNK stimulator, anisomycin, converts the protease mRNA levels from those characteristic of a CL-dependent to a uPA-dependent phenotype. These protease phenotypes can be duplicated in untransformed NIH 3T3 cells that express platelet-derived growth factor receptors and m1 muscarinic receptors that selectively stimulate the ERK or JNK pathways, respectively. It is concluded that high ERK activity is required for both protease phenotypes, whereas the JNK pathway and c-Jun/AP-1 activity are not required for transformation but regulate a switch between uPA and CL protease phenotypes in both transformed and untransformed cells. In ras-transformed NIH 3T3 fibroblasts, the uPA- and CL-dependent protease phenotypes are redundant in their ability to invade through basement membrane.
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PMID:Role of mitogen-activated protein kinases and c-Jun/AP-1 trans-activating activity in the regulation of protease mRNAs and the malignant phenotype in NIH 3T3 fibroblasts. 987 19

A consecutive series of 63 untreated patients undergoing surgical resection for stage I-IV gastric adenocarcinomas (GCs) has been prospectively studied. Our purpose was to analyze the predictive relevance of DNA ploidy, S-phase fraction (SPF), and tissue levels of lysosomal proteinases cathepsin D (CD), cathepsin B (CB), cathepsin L (CL), and urokinase-type plasminogen activator (uPA) and that of the intracellular cysteine proteinase inhibitor stefin A on clinical outcome. All of the patients taking part in this study were followed up for a median of 73 months. DNA aneuploidy was present in 71% of the cases (45/63), whereas 9% of these (4/45) showed multiclonality. Both DNA ploidy and SPF were associated with tumor-node-metastasis (TNM) stage and node status, whereas only DNA ploidy was related to depth of invasion. CB, CL, uPA, but not CD, levels were significantly higher in GC as compared to paired normal mucosa, whereas stefin A levels were lower in tumor tissues. CB levels were significantly associated with TNM stage, nodal status, histological grade, and DNA ploidy. At univariate analysis, only node involvement, advanced TNM stage, DNA aneuploidy, and high SPF proved to be significantly related to quicker relapse and to shorter overall survival, whereas depth of invasion was related only to survival. With multivariate analysis, only high SPF (>15.2%) was related to risk of relapse (RR = 8.50), whereas high SPF and DNA aneuploidy were independently related to risk of death (RR = 1.88 and 2.09, respectively). Our preliminary prospective study has identified SPF and DNA ploidy as important biological indicators for predicting the outcome of patients with GC.
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PMID:Prognostic significance of DNA ploidy, S-phase fraction, and tissue levels of aspartic, cysteine, and serine proteases in operable gastric carcinoma. 1065 48

Throughout spermatogenesis, germ cells move progressively from the basal to the adluminal compartment, which is accompanied by continual disassembly and reassembly of intercellular junctions suggesting germ cell movement is composed of intermittent phases of junction disassembly and reassembly. A study was performed to correlate the expression of junctional-complex components (such as zonula occludens-1 [ZO-1], a tight-junction component protein) and nonjunctional complex components (such as urokinase-type plasminogen activator [uPA], a serine protease; cathepsin L, a cysteine protease; alpha2-macroglobulin, a nonspecific protease inhibitor; and cystatin C, a cysteine protease inhibitor) at the time when inter-Sertoli tight junctions were established in vitro. This is an attempt to investigate whether the expression of nonjunctional component genes also correlates with the formation of inter-Sertoli tight junctions in vitro. This is part of an effort to understand the physiologic elements of germ cell movement in the epithelium. Sertoli cells cultured in vitro are known to undergo programmed cell death. To ensure that the changes in target gene expression were not the result of apoptosis, Sertoli cells were cultured in vitro at densities of 0.25, 0.75, and 3 x 10(6) cells/cm2 for up to 7 days on bicameral culture units coated with Matrigel (Collaborative Research) and were assessed by morphologic analysis and agarose gel electrophoresis. It was noted that many of the Sertoli cells cultured at 3 x 10(6) cells/cm2 underwent apoptosis by day 7, in contrast to cultures at 0.25 and 0.75 x 10(6) cells/cm2 illustrating the Sertoli cell number per unit of area may be an important parameter to be considered when studying Sertoli cell function in vitro. Also, it was shown that the expression of ZO-1 increased significantly between days 2 and 3 prior to the establishment of inter-Sertoli tight junctions assessed by transepithelial resistance measurement (TER), which illustrates that ZO-1 can be used as a marker to monitor this cellular event. More interestingly, there was also a transient increase in the expression of uPA and cathepsin L between days 2 and 3 at the time preceding the formation of tight junctions. In Sertoli cells cultured at low density (2 x 10(4) cells/cm2), when a confluent monolayer of cells could not form, there were no changes in the expression of either ZO-1, uPA, or cathepsin L throughout the 7-day culture period. These results show that the establishment of specialized junctions, such as tight junctions between Sertoli cells in vitro, may require the participation of both junctional and nonjunctional complex components.
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PMID:Changes in the expression of junctional and nonjunctional complex component genes when inter-sertoli tight junctions are formed in vitro. 1071 17

To clarify the pathophysiological role of cathepsins in rheumatoid arthritis (RA), we investigated whether cathepsin B or cathepsin L was increased in synovial fluid (SF) of RA joints, and whether the cathepsin isolated from SF of RA patients activated pro-urokinase or not. Thus, we estimated the content of cathepsins in SF of RA patients by measuring their activities by fluorospectrometry, using Z-Phe-Arg-MCA as the substrate. Cathepsin activity was approximately 4-fold higher in the SF of RA patients than in those of patients with osteoarthritis. Cathepsin B and cathepsin L were separated by cation-exchange column chromatography. As a result, a large peak corresponding to cathepsin B and a very small peak corresponding to cathepsin L were detected. Biochemical sequential fractionation of the cathepsin purified from the SF showed that the large peak was mainly composed of cathepsin B. This purified enzyme induced conversion of pro-urokinase to urokinase, and the Km for pro-urokinase was approximately 8.27 microM. These findings indicated that an imbalance between cathepsin B and its inhibitors occurred due to increased concentrations of active cathepsin B in RA articular lesions, and that cathepsin B might be related to the degradation of cartilage in RA by activating the fibrinolytic cascade.
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PMID:Cathepsins B and L in synovial fluids from patients with rheumatoid arthritis and the effect of cathepsin B on the activation of pro-urokinase. 1074 Sep 81

After long-term follow-up, the prognostic impact of the following proteolytic factors associated with tumor invasion and metastasis was evaluated in 276 primary breast cancer patients: uPA (urokinase-type plasminogen activator), PAI-1 (uPA inhibitor type 1), and cathepsins B, D and L. The median follow-up of patients still alive at the time of analysis was 109 months. To date 119 patients (43%) have relapsed and 117 (42%) have died. Antigen levels of uPA and PAI-1 were determined by ELISA in detergent extracts; cathepsin B, D, and L content was determined in cytosol fractions of the primary tumor: cathepsin D by ELSA and cathepsin B and L by ELISA. In multivariate analysis (Cox model) for disease-free survival (DFS), lymph node status (p < 0.001; RR = 3.8), cathepsin L (p < 0.001; RR = 2.6) and PAI-1 (p = 0.027; RR = 1.7) were significant factors in all patients. In addition to these factors, grading was significant for overall survival (OS). In another multivariate approach, CART (Classification And Regression Trees) analysis, lymph node status (p < 0.001) turned out to be the strongest discriminator for patients at high risk of relapse. In the node-negative patient subset, PAI-1 was the strongest risk group discriminator (p < 0.001): in this subset, patients with low levels of both PAI-1 and cathepsin D had a very low relapse rate of only 3.2% compared to 39% in the remaining node-negative patients. In node-positive patients cathepsin L gave the best risk group assessment (p = 0.001). In conclusion, tumor-associated PAI-1 and cathepsins D and L provide significant, statistically independent prognostic information for DFS and OS in primary breast cancer, even after a median follow-up period of almost 10 years.
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PMID:Long-term follow-up confirms prognostic impact of PAI-1 and cathepsin D and L in primary breast cancer. 1076 46

Cancer invasion and metastasis is a process requiring a coordinated series of (anti-)adhesive, migratory, and pericellular proteolytic events involving various proteases such as urokinase-type plasminogen activator (uPA)/plasmin, cathepsins B and L, and matrix metalloproteases. Novel types of double-headed inhibitors directed to different tumor-associated proteolytic systems were generated by substitution of a loop in chicken cystatin, which is nonessential for cysteine protease inhibition, with uPA-derived peptides covering the human uPA receptor binding sequence uPA-(19-31). The inhibition constants of these hybrids toward cysteine proteases are similar to those of wild-type cystatin (K(i), papain (pm), 1.9-2.4; K(i), cathepsin B (nm), 1.0-1.7; K(i), cathepsin L (pm), 0.12-0.61). FACS analyses revealed that the hybrids compete for binding of uPA to the cell surface-associated uPA receptor (uPAR) expressed on human U937 cells. The simultaneous interaction of the hybrid molecules with papain and uPAR was analyzed by surface plasmon resonance. The measured K(D) value of a papain-bound cystatin variant harboring the uPAR binding sequence of uPA (chCys-uPA-(19-31)) and soluble uPAR was 17 nm (K(D) value for uPA/uPAR interaction, 5 nm). These results indicate that cystatins with a uPAR binding site are efficient inhibitors of cysteine proteases and uPA/uPAR interaction at the same time. Therefore, these compact and small bifunctional inhibitors may represent promising agents for the therapy of solid tumors.
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PMID:A novel type of bifunctional inhibitor directed against proteolytic activity and receptor/ligand interaction. Cystatin with a urokinase receptor binding site. 1091 10

In our previous work we showed that the drug-resistance of cervical carcinoma, laryngeal carcinoma and glioblastoma cells may be accompanied by increased levels of tumor markers for invasion and metastasis (i.e. urokinase-type plasminogen activator, plasminogen activator inhibitor type 1, and/or cathepsin D). In the present study we examined the concentration of cathepsins B, L and H in three drug-resistant clones isolated from human laryngeal carcinoma (HEp2). The basal levels of cathepsins B, L and H were determined by enzyme linked immunoabsorbent assay (ELISA). Our results showed that all three clones had an increased level of cathepsin B (in two clones an almost 4-fold increase was determined). The level of cathepsin L was altered (increased) only in VK2 clone, while the levels of cathepsin H were similar in parental cells and drug-resistant clones. Thus, our results suggest that drug-resistance may be accompanied by an increased level of cathepsin B, i.e. tumor associated protease, involved in invasion and metastasis.
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PMID:Drug-resistant human laryngeal carcinoma cells have increased levels of cathepsin B. 1129 83

Cysteine, serine and metalloproteinases and their respective inhibitors are involved in tumor cell invasion and may have prognostic value for the outcome of malignant disease. The aim of the study was to compare the expression of new potential biological tumor markers, the lysosomal cysteine proteinases and their endogenous inhibitors, with that of the serine proteinases and their inhibitors in breast cancinoma and to relate their levels to the clinicopathological factors of the disease. Enzyme-linked immunosorbent assays (ELISAs) were used to measure cysteine cathepsin B (CatB) and cathepsin L (CatL) and their inhibitors, stefin A (StA) and stefin B (StB), together with urokinase (u-PA) and plasminogen activator inhibitor-1 (PAI-1), in 150 cytosols of primary invasive breast carcinoma. A good correlation was found between the levels of the two cysteine proteinases but only a moderate one between those of the cysteine and serine proteinases. u-PA and PAI-1 levels correlated positively with histological grade and negatively with estrogen receptor (ER) status. PAI-1 correlated with most clinicopathological factors that indicate the progression of the disease, while cathepsins and stefins were independent of these factors. In the total group of patients, high u-PA and PAI-1 and low StB levels correlated significantly with shorter disease-free survival (DFS), while CatB, CatL and StA did not. In lymph node negative patients, high CatB and CatL were also associated with shorter DFS, while u-PA remained the most significant of all these biological markers. In conclusion, this retrospective study showed u-PA to be of better prognostic relevance than the cysteine proteinases, though CatB and CatL were relevant for prognosis in lymph node negative breast cancer patients.
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PMID:Comparison of potential biological markers cathepsin B, cathepsin L, stefin A and stefin B with urokinase and plasminogen activator inhibitor-1 and clinicopathological data of breast carcinoma patients. 1208 2

The passage of leukocytes through basement membranes involves proteolytic degradation of extracellular matrix (ECM) components executed by focalized proteolysis. We have investigated whether the migration of leukocytes through 3-dimensional collagenous tissue scaffolds requires similar ECM breakdown. Human T blasts and SupT1 lymphoma cells expressed mRNA of MMP-9, MT1-MMP, MT4-MMP, cathepsin L, uPA, and uPAR as well as ADAM-9, -10, -11, -15, and -17. Upon long-term migration within 3-dimensional collagen matrices, however, no in situ collagenolysis was obtained by sensitive fluorescein isothiocyanate-collagen fragmentation analysis and confocal fluorescence/backscatter microscopy. Consistent with nonproteolytic migration, T-cell crawling and path generation were not impaired by protease inhibitor cocktail targeting MMPs, serine proteases, cysteine proteases, and cathepsins. Dynamic imaging of cell-ECM interactions showed T-cell migration as an amoeba-like process driven by adaptive morphology, crawling along collagen fibrils (contact guidance) and squeezing through pre-existing matrix gaps by vigorous shape change. The concept of nonproteolytic amoeboid migration was confirmed for multicomponent collagen lattices containing hyaluronan and chondroitin sulfate and for other migrating leukocytes including CD8+ T blasts, monocyte-derived dendritic cells, and U937 monocytic cells. Together, amoeboid shape change and contact guidance provide constitutive protease-independent mechanisms for leukocyte trafficking through interstitial tissues that are insensitive toward pharmacologic protease inhibitors.
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PMID:Amoeboid shape change and contact guidance: T-lymphocyte crawling through fibrillar collagen is independent of matrix remodeling by MMPs and other proteases. 1285 77


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