Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of protein kinase C- (PKC) and Fos/Jun-dependent signal transduction pathways are thought to be major effects of oncogene action in different tumor systems including human non-small-cell lung carcinoma (NSCLC). We have previously shown that the phorbol ester analogue phorbol-myristate-acetate (PMA), which is a potent activator of PKC, can induce squamous-type cellular differentiation and the expression of proteinases, such as plasminogen activators and pro-cathepsin L, in several NSCLC cell lines. To investigate the PMA-dependent effect on proteinase secretion in more detail, we have now analysed the role of a downstream transmitter of PKC activity in this process, namely Fos, which is part of the AP-1 transcription factor in the nucleus. We transfected a cell line derived from an undifferentiated squamous-cell lung carcinoma with different chimeric fos-estrogen receptor constructs (fos-ER) which makes selective activation of this transcription factor possible. The resulting clones were treated either with PMA as activator of PKC, or with diethylstilbestrol (DES), an estrogen analogue binding to and thereby activating preformed Fos-ER molecules. We show that cells treated with either substance undergo similar phenotypic changes (change from cuboidal to spindle-cell type) and decrease their doubling rates and cloning efficiencies. This is paralleled by the induction of several proteinase genes such as t-PA, urokinase, and pro-cathepsins B and L. Contrary to activated PKC, Fos in this system seems to be unable to initiate terminal squamous-cell differentiation, as assessed by the production of cornified envelopes. It is, however, efficient in the stimulation of neutral or lysosomal proteinase secretion as determined by Western-blot analysis and zymography. This Fos-ER expressing system thus seems to be a valuable tool in the molecular dissection of pathways that lead to the activation and secretion of proteinases in NSCLC cells.
 ...
PMID:Control of proteinase expression by phorbol-ester- and Fos-dependent pathways in human non-small-cell lung-cancer cells. 913 54

Plasminogen activation has been proposed to play a critical role in cancer invasion and metastasis. The effects of complete ablation of plasminogen activation in cancer was studied by inoculation of a metastatic Lewis lung carcinoma expressing high levels of plasminogen activator into plasminogen-deficient (Plg-/-) mice and matched control mice. Primary tumors developed in all mice with no difference in the rate of appearance between Plg-/- and control mice. However, the primary tumors in Plg-/- mice were smaller and less hemorrhagic and displayed reduced skin ulceration. In addition, dissemination of the tumor to regional lymph nodes was delayed in Plg-/- mice. Surprisingly, no quantitative differences were observed in lung metastasis between Plg-/- and control mice. In addition, Plg deficiency was compatible with metastasis of the primary tumor to a variety of other organs. Nevertheless, Plg-/- mice displayed a moderately increased survival after primary tumor resection. These findings suggest that plasmin-mediated proteolysis contributes to the morbidity and mortality of Lewis lung carcinoma in mice, but sufficient proteolytic activity is generated in Plg-/- mice for efficient tumor development and metastasis.
 ...
PMID:Growth and dissemination of Lewis lung carcinoma in plasminogen-deficient mice. 937 63

Angiostatin, a potent naturally occurring inhibitor of angiogenesis and growth of tumor metastases, is generated by cancer-mediated proteolysis of plasminogen. Human prostate carcinoma cells (PC-3) release enzymatic activity that converts plasminogen to angiostatin. We have now identified two components released by PC-3 cells, urokinase (uPA) and free sulfhydryl donors (FSDs), that are sufficient for angiostatin generation. Furthermore, in a defined cell-free system, plasminogen activators [uPA, tissue-type plasminogen activator (tPA), or streptokinase], in combination with one of a series of FSDs (N-acetyl-L-cysteine, D-penicillamine, captopril, L-cysteine, or reduced glutathione] generate angiostatin from plasminogen. An essential role of plasmin catalytic activity for angiostatin generation was identified by using recombinant mutant plasminogens as substrates. The wild-type recombinant plasminogen was converted to angiostatin in the setting of uPA/FSD; however, a plasminogen activation site mutant and a catalytically inactive mutant failed to generate angiostatin. Cell-free derived angiostatin inhibited angiogenesis in vitro and in vivo and suppressed the growth of Lewis lung carcinoma metastases. These findings define a direct mechanism for cancer-cell-mediated angiostatin generation and permit large-scale production of bioactive angiostatin for investigation and potential therapeutic application.
 ...
PMID:The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. 938 Jul 26

Although fibrinolysis has been implicated in the progression and metastasis of lung cancer, no detailed study has been carried out on components measured in samples from both plasma and tumour. This study thus provides the first comprehensive data obtained from 166 patients diagnosed with non-small cell lung carcinoma. Plasma samples were obtained at diagnosis and tumour samples during surgical resection. Appropriate control samples were obtained from normal subjects and patients with chronic obstructive airways disease (plasma) and from organ donors (normal lung tissue). Assays were performed on plasma and tissue extracts for tissue plasminogen activator, urokinase-like activator and plasminogen activator inhibitor (activity and antigen in all cases), together with plasmin-antiplasmin complex, soluble fibrin, D-dimer and thrombin-antithrombin complex. Levels of D-dimer, thrombin-antithrombin complex and plasmin-antiplasmin complex were all significantly higher in plasma from patients, whereas urokinase-like activator activity was reduced. Only two parameters were significantly altered in both the core and periphery of tumour tissue: levels of D-dimer were increased and tissue-type plasminogen activator activity was reduced. Interestingly, significant differences in levels of other fibrinolytic parameters were detected in the core and periphery of tumours. Significant activation of fibrinolysis was indicated in patients, although the origin of this could not be related consistently to changes in levels of plasminogen activator and inhibitor.
 ...
PMID:Alterations to the fibrinolytic enzyme system in patients with non-small cell lung carcinoma. 1045 17

Oncostatin M (OSM) is a glycoprotein cytokine that is produced by activated T-lymphocytes, monocytes, and macrophages. In a DNA synthesis assay, OSM reduced tritiated thymidine incorporation by 53% in Calu-1 lung carcinoma cells. Radiolabeled cDNAs from untreated Calu-1 cells and 30-h OSM-treated cells were used to probe duplicate nylon membrane cDNA expression arrays. This study revealed OSM-mediated expression of mRNAs encoding tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1). Northern blot analysis showed that the steady-state level of tPA mRNA is nearly undetectable in Calu-1 cells. Exposure of these cells to OSM for 30 h increased tPA mRNA expression by 20-fold and PAI-1 mRNA expression by 5-fold. Exposure of these cells to other gp130 receptor family cytokines, including leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and IL-11, do not significantly affect DNA synthesis or induction of tPA/PAI-1. Western blot studies demonstrated that OSM mediates a marked increase in secretion of the tPA protein. Secreted tPA was present in the conditioned medium almost exclusively as tPA/PAI-1 complexes. Inhibitor studies demonstrated that OSM-mediated induction of tPA and PAI-1 mRNAs is largely dependent upon activation of the MEK1/2 pathway. The JAK3/STAT3 pathway potentially serves a secondary role in these regulatory events.
 ...
PMID:Oncostatin M induces tissue-type plasminogen activator and plasminogen activator inhibitor-1 in Calu-1 lung carcinoma cells. 1209 Jul 57

To study the behavior and possible correlations of neuron-specific enolase (NSE) with other clinicobiological parameters, we measured the cytosolic levels of this marker by means of an immunoradiometric assay (IRMA) in 95 squamous cell lung carcinoma samples. We also analyzed the levels of pS2, tissue-type plasminogen activator (t-PA), hyaluronic acid (HA), free beta subunit of human chorionic gonadotropin (beta-HCG), CYFRA 21.1 and CA 125 in cytosol. On the cell surface we analyzed the concentrations of epidermal growth factor receptor (EGFR), HA, erbB-2 oncoprotein, CD44s, CD44v5 and CD44v6. Other parameters considered were clinical stage, lymph node involvement, histological grade (HG), ploidy and the cellular S-phase fraction measured by flow cytometry on nuclei obtained from fresh tissues. In the 95 squamous cell carcinomas the cytosolic levels of NSE varied from 4.5 to 2235 ng/mg protein (median: 267) and were significantly higher (p < 0.001) than those observed in 38 samples of normal pulmonary tissue obtained from the same patients (range: 56-657; median: 141.5). When classifying tumors according to the different parameters analyzed, we observed that the levels of NSE were higher in aneuploid than in diploid cases (p = 0.046) and in those that were HG3 than in those that were HG2 (p < 0.001). Tumors with high NSE levels (> 422 ng/mg protein; 75th percentile) were more likely to have high S-phase values (p = 0.012) and were more frequently aneuploid (p = 0.038) and HG3 (p < 0.001) than those with low levels of NSE (< 180 ng/mg protein; 25th percentile). These results lead us to the following conclusions: 1) the cytosolic concentrations of NSE are significantly higher in squamous cell carcinomas than in healthy pulmonary tissue, and 2) the cytosolic concentrations of NSE are not correlated with clinical stage or nodal involvement. However, in our study higher levels of the enzyme were statistically correlated with aneuploidy, histological grade 3 and S-phase. This may explain its association with poorer outcome and progression, but also the more favorable response of tumors with elevated NSE to chemotherapy, as suggested by other groups.
 ...
PMID:Cytosolic levels of neuron-specific enolase in squamous cell carcinomas of the lung. 1453 89

The proto-oncogene Ets-1 is a transcription factor that is known to regulate certain matrix metalloproteinases and plasminogen activator, which have been associated with malignant behaviors in solid carcinomas. We hypothesized that Ets-1 expression is also associated with tumor progression and a worse prognosis in lung carcinoma patients. To clarify the role of the Ets-1 proto-oncogene, the expression of Ets-1 in non-small cell lung carcinomas using 156 paraffin-embedded specimens was determined in surgically resected tissue samples. Immunohistochemical staining showed Ets-1 expression in 82 cases of 156 carcinomas (53%): 36 of 52 (69%) squamous cell carcinomas, 41 of 96 (43%) adenocarcinomas, and 5 of 8 (63%) other carcinomas. In adenocarcinomas, a higher proportion of acinar type expressed Ets-1 compared to papillary or alveolar type (p < 0.05). The proportion of adenocarcinoma that expressed Ets-1 increased with poorer histologic differentiation of the adenocarcinoma (p < 0.05). Ets-1 positive adenocarcinomas had a larger mean size than Ets-1 negative adenocarcinomas (p < 0.01). In adenocarcinoma patients, expression of Ets-1 was associated with disease-free (p = 0.09) and overall survivals (p < 0.05) after lung resection. Such relationship was not observed among squamous cell carcinoma patients. Our findings indicate that Ets-1 expression is related to histopathological differentiation, morphogenesis, and tumor progression of lung adenocarcinomas. Ets-1 appears to be a useful predictor of poor prognosis after surgical resection in lung adenocarcinoma patients. Ets-1 expression could be used to evaluate the malignant behaviors of lung adenocarcinomas.
 ...
PMID:Ets-1 proto-oncogene as a potential predictor for poor prognosis of lung adenocarcinoma. 1778 52

Human single-chain tissue-type plasminogen activator (tPA) was activated by the culture media of mouse B16 melanoma and Lewis lung carcinoma cells. This activation was due to the proteolytic conversion of single-chain tPA to two-chain tPA. Typical serine proteinase inhibitors, such as diisopropylfluorophosphate and aprotinin, strongly inhibited the proteolytic activation, suggesting that the enyzme responsible for this activation is a serine proteinase. Through a process of gel filtration, the molecular weight of the putative tPA-activating enzyme was estimated to be approximately 35 kDa. Expression of the tPA mRNA was demonstrated by Northern blot analysis both for the melanoma and carcinoma cells. Zymographic experiments showed that the culture medium of the melanoma cells contained active two-chain tPA. These results indicate that a common serine proteinase may be involved in the proteolytic activation of single-chain tPA in these cancer cells.
 ...
PMID:Proteolytic activation of tissue-type plasminogen activator by the culture media of mouse cancer cells. 1846 28

The plasminogen pathway plays an important role in the behavior of many tumors including lung cancer. Hence genetic variants encoding plasminogen activator (PLAU), plasminogen receptor (PLAUR), plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2) may contribute to lung cancer prognosis. To investigate this proposition we genotyped PAI-1 A15T, PLAU L141P, PLAUR L317P and PAI-2 S413C variants in 698 patients with lung cancer, 522 with non-small cell (NSCLC) and 176 with small cell lung cancer (SCLC). PAI-1 A15T was significantly associated with overall survival (OS), with carriers of variant alleles having a worse prognosis (hazard ratio (HR)=1.14; 95% confidence interval [CI]: 1.03-1.26). An association was also detected between OS in NSCLC and carrier status for PAI-2 413C (HR=1.13; 95% CI: 1.01-1.24). These common genetic variants identified warrant further evaluation as promising prognostic markers of patient outcome.
Lung Cancer 2009 Aug
PMID:Plasminogen activator inhibitor variants PAI-1 A15T and PAI-2 S413C influence lung cancer prognosis. 1911 38

Some Ru(II)-DMSO complexes have antimetastatic properties in experimental tumors. Since plasminogen activators are thought to play an important role in the expression of cancer cell metastatic capacity, we evaluated the effect of two Ru(II)-DMSO complexes on the fibrinolytic activity of Lewis lung carcinoma. Tumor-bearing mice were given daily, for 14 days, an i.p. injection of antimetastatic dosages of cis-RuCl2(DMSO)4 (700 mg/kg/die) or trans-RUCl2(DMSO)4 (37 mg/kg/die), or vehicle. Tumor extracts obtained on day 15 from treatment groups had significantly lower (plasminogen-dependent) fibrinolytic activity than extracts from control animals (p<0.001). Urokinase inhibitor activity in tumor extracts did not differ among groups and did not correlate with plasminogen activator activity, Fibrin autography of control tumor extracts revealed the presence of a main fibrinolytic band co-migrating with urinary plasminogen activator (urokinase-type) and of minor bands with a higher molecular weight. In samples from animals treated with either Ru(II)-DMSO complex the most striking finding was a reduction of the band corresponding to free urokinase. These findings suggest that ruthenium complexes decrease the fibrinolytic activity of tumor cells by reducing urokinase production rather than by enhancing inhibitor production. Treatment of tumor-bearing mice with cis-RuCl2(DMSO)4 at a dosage equimolar to the trans isomer, neither reduced metastasis formation nor decreased plasminogen activator activity of tumor extracts. The depression of tumor-associated proteolytic activity could contribute to the antimetastatic properties of ruthenium complexes.
 ...
PMID:Reduction of tumor-associated fibrinolytic-activity by antimetastatic dosages of 2 ru(ii)-dmso complexes in mice bearing lewis lung-carcinoma. 2157 87


<< Previous 1 2 3 4 Next >>