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)

Cytotoxicity indicated by increased release of prelabeled 51chromium (51Cr) and lactate dehydrogenase (LDH) was studied in human prostate cancer and melanoma cells in cell culture following irradiation or exposure to several injurious substances. These changes were compared to those observed in bovine aortic endothelial cells (BAEC) subjected to identical treatments. Further, the effect of irradiation on plasminogen activator (PA) secretion from prostate cancer cells, and the effect of glycine on radiation-induced cytotoxicity in BAEC were also investigated. Radiation, lipopolysaccharide and xanthine/xanthine oxidase stimulated no release of 51Cr or LDH from tumor cells, while these treatments induced a dose- and time-related loss of those cytotoxic indicators from BAEC. Protease, elastase and Triton X-100 incited loss of 51Cr and LDH from all three cell types. Radiation, lipopolysaccharide and xanthine/xanthine oxidase have been shown to cause cell injury via a common pathogenic pathway of oxidant generation. Tumor cells appear quite resistant to oxidant stress. Cell damage precipitated by protease, elastase and Triton probably involves hydrolysis of proteins and phospholipids in the cell membrane, leading to an increased leakage of intracellular proteins such as LDH and those bound with 51Cr. Radiation caused a dose- and time-related reduction in the secretion of PA from prostate cancer cells. PA is alleged to play a role in tumor metastasis; the reduced secretion could be another beneficial effect of radiation, in addition to interruption of cell proliferation, in the impediment of tumor growth and spread. Glycine diminished cytotoxic injury of BAEC inflicted by radiation. This amino acid may prove useful in offering a degree of protection of normal tissue against radiation associated side-effects.
 ...
PMID:Injury-specific cytotoxic response of tumor cells and endothelial cells. 868 34

The binding of urokinase-type plasminogen activator (u-PA) to a specific cell surface receptor (uPA-R) has been shown to enhance plasminogen activation, a process involved in extracellular matrix degradation and cell migration during angiogenesis and tumor growth. We investigated the expression of u-PA and uPA-R in renal cell carcinomas (n = 11). By immunohistochemistry using monoclonal and polyclonal anti-uPA-R antibodies, we found that tumoral capillary endothelial cells (von Willebrand factor and CD31 positive cells) overexpressed uPA-R, whereas vascular endothelial cells of the normal human kidney do not. In addition, tumor-associated macrophages (CD68-positive cells) strongly expressed uPA-R. In contrast, few tumoral cells and stromal fibroblasts expressed uPA-R. By in situ hybridization using a cDNA S35-labeled probe specific for uPA-R, we confirmed the local expression of uPA-R messenger RNA. We also detected the induction of u-PA in tumoral capillary endothelial cells and in tumor-associated macrophages. In two cases, tumoral cells themselves were also stained by anti-u-PA antibodies in focal areas. Finally tissue-type plasminogen activator (t-PA) was also overexpressed by tumoral capillary endothelial cells as compared with endothelial cells of normal human kidney vessels. These findings indicate an active invasive phenotype of endothelial cells in renal cell carcinoma and suggest a role for the plasminogen activation system in tumoral angiogenesis and invasion.
 ...
PMID:Endothelial and macrophage upregulation of urokinase receptor expression in human renal cell carcinoma. 902 4

Glucocorticoid (GC) use is known to induce or enhance the growth of Kaposi's sarcoma (KS) in many clinical settings including human immunodeficiency virus infection, collagen vascular disease, lymphoproliferative disorders, and renal transplantation. Because GCs may induce immune suppression and thus tumor growth, we determined whether GCs had a direct effect on KS growth. We found that GCs directly induce the growth of KS cell lines. In examining the mechanism of action of GCs, we did not observe induction of known autocrine growth factors for KS including interleukin-1 (IL-1), IL-6, oncostatin-M, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF). We thus examined factor(s) that inhibit KS growth. Transforming growth factor-beta (TGF-beta) is produced by KS cells and has pleiotropic effects, including inhibiting the growth of hematopoietic and endothelial cells. We show that TGF-beta is produced by KS cells in both the latent and active forms, and that TGF-beta is an autocrine growth inhibitory factor. We then studied the effects of GCs on the regulation of TGF-beta and found that GCs do not inhibit TGF-beta transcription, but significantly inhibit TGF-beta activation. This effect is mediated through regulation of the TGF-beta activation pathway. TGF-beta is activated by plasmin which is positively regulated by plasminogen activator (PA) and PA receptor (PAR), and negatively regulated by plasminogen activator inhibitor (PAI). GCs downregulated PAR and upregulated PAI. Thus, glucocorticoids enhance KS cell growth through the regulation of TGF-beta activation.
 ...
PMID:Glucocorticoids induce Kaposi's sarcoma cell proliferation through the regulation of transforming growth factor-beta. 905 28

Cytogenin (8-hydroxy-3-hydroxymethyl-6-methoxyisocoumarin) is a new microbial product with antitumor and antirheumatoid arthritis effects in vivo when administered orally, although its mechanism(s) of action is not known well. Both neoplasia and rheumatoid arthritis are referred to as angiogenesis-dependent diseases. The aim of the present study was to investigate the effects of cytogenin on both physiological and pathological angiogenesis, using the growing chick embryo chorioallantoic membrane and mouse dorsal air sac assay systems, respectively. The microbial product at doses up to 100 micrograms/egg did not significantly affect embryonic angiogenesis when topically placed on the surface of the chorioallantoic membrane, suggesting that it has no effect on the physiological (or normal) angiogenic response. By contrast, systemic administration of cytogenin (100 mg/kg p.o., for 5 consecutive days) significantly suppressed angiogenesis induced by malignant tumor cells (S-180), one of pathological neovascularization, in a mouse dorsal air sac assay system. Pharmacokinetic studies in mice revealed that the maximal concentration of cytogenin in plasma after a single 100 mg/kg oral dose of the compound was 32 microM. In vitro experiments involving cultured vascular endothelial cells showed that cytogenin at concentrations determined by pharmacokinetic study, had little effect on plasminogen activator secretion, tube formation and the proliferation of endothelial cells. These results suggest that cytogenin is a novel oral antiangiogenic agent, that the mechanism of its antiangiogenic action contributes to its suppressive effects on both tumor growth and rheumatoid arthritis that we previously found, and that it could be developed as a potential therapeutic agent for cancer, rheumatoid arthritis and other angiogenesis-dependent disorders such as diabetic retinopathy.
 ...
PMID:Effects of cytogenin, a novel microbial product, on embryonic and tumor cell-induced angiogenic responses in vivo. 921 39

Various proteases and their inhibitors have been shown to be important in tumor invasion. Angiogenesis is further a prerequisite for the growth and progression of solid tumors. Since these systems are functionally linked, in situ hybridization and in situ zymography were used to investigate the spatial and temporal expression of factors representative of the plasmin/plasminogen system and of an angiogenic factor in the BT4C glioma model. This tumor is invasive with a high grade of neovascularization. Tissue-type plasminogen activator urokinase-type plasminogen activator and plasminogen activator inhibitor-1 mRNA were expressed in glioma cells during the entire tumor growth. Early in the tumor development the expression was found throughout the small tumor (approximately 10 mm3) while later in the time course the expression was found predominantly in the invasive tumor border of the tumor. The in situ zymography demonstrated that the plasminogen activators were translated into functional proteins. Vascular endothelial growth factor mRNA was expressed following a similar spatial and temporal pattern with an early expression in the entire small tumor while later, in larger tumors, it was exclusively expressed in the invasive tumor edge. In normal brain, the ventricular ependyma, meninges, as well as scattered neurons expressed tissue-type plasminogen activator mRNA. Vascular endothelial growth factor mRNA was observed in the choroid plexus, and in scattered cells in normal brain tissue. Our finding may suggest a functional co-operation of tissue-type plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor-1 and vascular endothelial growth factor during glioma progression. This model could be of value when evaluating different treatment modalities aimed at blocking the migrating capacity and growth of glial tumors.
 ...
PMID:Expression of the proteolytic factors, tPA and uPA, PAI-1 and VEGF during malignant glioma progression. 1057 9

The plasminogen (Plg)/plasminogen activator (PA) system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumor cell migration. Consequently, urokinase-type PA (uPA)/plasmin antagonists are currently being developed for suppression of tumor growth and angiogenesis. Paradoxically, however, high levels of PA inhibitor 1 (PAI-1) are predictive of a poor prognosis for survival of patients with cancer. We demonstrated previously that PAI-1 promoted tumor angiogenesis, but by an unresolved mechanism. We anticipated that PAI-1 facilitated endothelial cell migration via its known interaction with vitronectin (VN) and integrins. However, using adenoviral gene transfer of PAI-1 mutants, we observed that PAI-1 promoted tumor angiogenesis, not by interacting with VN, but rather by inhibiting proteolytic activity, suggesting that excessive plasmin proteolysis prevents assembly of tumor vessels. Single deficiency of uPA, tissue-type PA (tPA), uPA receptor, or VN, as well as combined deficiencies of uPA and tPA did not impair tumor angiogenesis, whereas lack of Plg reduced it. Overall, these data indicate that plasmin proteolysis, even though essential, must be tightly controlled during tumor angiogenesis, probably to allow vessel stabilization and maturation. These data provide insights into the clinical paradox whereby PAI-1 promotes tumor progression and warrant against the uncontrolled use of uPA/plasmin antagonists as tumor angiogenesis inhibitors.
 ...
PMID:The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. 1126 68

Extracellular proteolysis is an absolute requirement for new blood vessel formation (angiogenesis). This review examines the role of the matrix metalloproteinase (MMP) and plasminogen activator (PA)-plasmin systems during angiogenesis. Specifically, a role for gelatinases (MMP-2, MMP-9), membrane-type 1 MMP (MMP-14), the urokinase-type PA receptor, and PA inhibitor 1 has been clearly defined in a number of model systems. The MMP and PA-plasmin systems have also been implicated in experimental vascular tumor formation, and their role during this process will be examined. Antiproteolysis, particularly in the context of angiogenesis, has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization.
 ...
PMID:Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. 1145 38

Extracellular proteolysis is an absolute requirement for new blood vessel formation, a process known as angiogenesis. This review will examine the role of the matrix metalloproteinase and plasminogen activator/plasmin systems during angiogenesis. Extracellular proteolysis has also been implicated in the generation of molecules with angioregulatory activity. These include, but are not limited to, angiostatin and endostatin. However, despite an abundance of data on their bioactivity, the molecular mechanisms by which these molecules achieve their effects are unknown. Anti-proteolysis, particularly in the context of angiogenesis, has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization.
 ...
PMID:Extracellular proteolysis and angiogenesis. 1148 24

One of the potential therapeutic interventions to hormone-independent breast cancer would be to reactivate the expression of estrogen receptor or progesterone receptor (PR) in the tumor cells so as to render the tumor responsive to the hormones. We have reported previously that progesterone markedly inhibited cell growth and induced remarkable focal adhesions in PR-transfected MDA-MB-231 cells. The aim of this study was to determine the effects of progesterone on the invasive properties and in vivo tumor growth of PR-transfected MDA-MB-231 cells. It was found that progesterone has increased cell resistance to trypsin digestion and increased cell attachment to extracellular matrix proteins, especially laminin and fibronectin. In vitro invasion assays using modified Boyden chambers showed that progesterone increased cell migration through matrix protein-coated membranes. However, Northern blotting analysis demonstrated that progesterone strongly down-regulated (up to 60-fold) the gene expression of urokinase plasminogen activator and increased (up to 5-fold) the expression of tissue-type plasminogen activator in these cells. This pattern of gene regulation suggested an inhibition of cell invasiveness because numerous clinical studies have indicated that low levels of urokinase plasminogen activator and high levels of tissue-type plasminogen activator in breast cancer are associated with favorable prognosis. Furthermore, animal studies showed that progesterone strongly inhibited the tumor formation and growth in Scid mice. After 12 weeks of inoculation, the median weight of tumors in the progesterone-treated group was 25 mg compared with 203 mg in the placebo group (P < 0.001). These results suggest that progesterone may provide effective treatment for estrogen receptor- and PR-negative breast cancer if the PR expression were reactivated. Alternatively, activation of progesterone-mediated molecular pathways in hormone-independent breast cancer may achieve similar therapeutic effects.
 ...
PMID:Effect of progesterone on the invasive properties and tumor growth of progesterone receptor-transfected breast cancer cells MDA-MB-231. 1155 6

Plasminogen can be converted to plasmin either via the tissue-type plasminogen activator (t-PA) or via the urokinase-type plasminogen activator (u-PA)/u-PA receptor (u-PAR) pathway. A dual role for these pathways is now well established: 1) t-PA is involved in fibrin homeostasis and 2) u-PA is primarily involved in cell migration and tissue remodeling. t-PA mediated activation is used for thrombolytic therapy of acute myocardial infarction and some other thromboembolic diseases. The u-PA mediated pathway, in concert with the matrix metalloproteinase (MMP) system, plays a pleiotropic role in arterial neointima formation, atherosclerosis, angiogenesis, tumor growth metastasis, and infarction. However, therapeutic interventions in the u-PA/MMP system remain to be further defined.
 ...
PMID:Ham-Wasserman lecture: role of the plasminogen system in fibrin-homeostasis and tissue remodeling. 1172 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>