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)

Proteolytic activities were measured in extracts of human skin melanoma, lymphatic metastasis and in nonmalignant naevi by using various proteinase substrates as well as plasminogen activator assay. pH-optima for hydrolysis of various proteinase substrates by these tumors were found to be essentially the same as in healthy human skin. Melanoma extracts were found to especially readily hydrolyze N-alpha-benzoyl-DL-arginine beta-naphthylamine (BANA) at pH 5.8 in the presence of 1 mmol/l dithiothreitol and EDTA (cathepsin B1-like enzyme) as well as histones and p-tosyl-L-arginine methyl ester (TAME) at pH 7.5, and showed increased capacity to activate plasminogen when compared to nonmalignant naevus. The possible role of proteinases in malignant melanoma is discussed.
 ...
PMID:Proteolytic enzymes and plasminogen activator in melanoma. 3 88

Cell clones derived from a human melanoma metastasis selected for different integrin profiles were examined in vitro for invasive potential and biological and biochemical features potentially related to this process. Clones which expressed high levels of integrins showed high invasive potential, extracellular matrix degradation, and adhesion to gelatin-coated substrates. A correlation was also found between invasiveness and intracellular and extracellular plasminogen activator activity. Heparanase and collagenase type IV activities were apparently unrelated to invasiveness. gamma-Glutamyl transferase (GGT) activity was high in highly invasive clones, whereas melanin content was high in slightly invasive clones. Heterogeneity was also observed in cellular parameters such as cell dimensions, growth features and DNA index. The intrinsic biological and biochemical heterogeneity of a cell population derived from a single metastasis may be responsible for the different behaviour of clones, regardless of their invasive potential. Since slightly invasive cells are more differentiated than highly invasive cells, malignancy and differentiation are inversely correlated in such human melanoma clones.
Melanoma Res 1992 Dec
PMID:Biological and enzymatic features of human melanoma clones with different invasive potential. 136 80

The tissue-destructive proteinases of B16-BL6 melanoma cells from C57BL/6 mice and subcellular fractions were examined. Cancer cell organelles were isolated following nitrogen cavitation with the use of sucrose density gradient centrifugation. Serine, cysteine, and metalloproteinases were assayed with the use of radiolabeled proteins and synthetic substrates. Tumor-induced red blood cell lysis was quantitated by measurement of the release of isotope from 59Fe-labeled red blood cells (RBC) cocultivated with melanoma cells; the RBC were from Wistar rats. Enzyme inhibitors with specificity toward different classes of proteinases were used in the above assays to categorize the enzymes responsible for substrate degradation. Results indicated that intact melanoma cells, cell organelles, and cytosol contain proteinases that can degrade collagen and gelatin and lyse normal RBC. Melanoma plasma membranes are highly enriched in collagenase, gelatinase, cysteine proteinase, plasminogen activator, and cytolytic activity. The inhibition of tumor collagenolytic, gelatinolytic, and cytolytic activities by EDTA and 1,10-phenanthroline but not by diisopropyl fluorophosphate and N alpha-p-tosyl-L-lysine chloromethyl ketone indicates that metalloproteinases are the active enzymes in these assays. Minocycline, a synthetic tetracycline with demonstrable inhibitory activity with other mammalian collagenases, also inhibited melanoma collagenolytic and cytolytic activities.
 ...
PMID:Diversity of melanoma plasma membrane proteinases: inhibition of collagenolytic and cytolytic activities by minocycline. 299 28

Proteases and their inhibitors have been shown to play roles in tumor invasion and metastasis in a number of experimental models. Recently, relative increases in the amounts of urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in tumor samples have been correlated with poorer, pathological grade, shorter disease-free interval, and shorter survival. To date, all studies investigating the prognostic significance of proteases and their inhibitors have been limited to extracranial cancer. In this article, we review the literature and present our data on the prognostic significance of proteases in human brain tumors. High levels of uPA were seen in malignant glioma and metastatic tumors (n = 82), whereas normal levels of uPA were found in low-grade gliomas. Analysis with magnetic resonance imaging (MRI) demonstrated a significant correlation between high levels of uPA and necrosis and edema (n = 50; P < 0.05). Similarly, patients with high levels of uPA had shorter survival than did patients with low levels of uPA. Tissue-type plasminogen activator (tPA), which was virtually absent in glioblastoma multiforme (GBM), colon lung, and breast metastasis, was found in normal quantities in anaplastic astrocytoma (AA), low-grade glioma (LGG), and meningioma. Melanoma had significantly more tPA activity than normal brain did. A reverse correlation was found between tPA and MRI findings of necrosis, enhancement, and edema. Similarly, patients with no detectable tPA activity had shorter survival than did patients with detectable tPA activity. We conclude that high levels of uPA and absent tPA activity correlate with histologically malignant brain tumors, aggressive characteristics, and shorter survival.
 ...
PMID:Prognostic significance of proteolytic enzymes in human brain tumors. 753 61

In an attempt to define the role of plasminogen activator in invasiveness and differentiation of human melanoma cells, the modulation of these parameters was studied in two melanoma clones characterized by marked differences in their basal features, using 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and retinoic acid, two differentiation inducers, and doxorubicin, a cytotoxic agent. TPA induced only slight reductions, whereas retinoic acid and doxorubicin caused an increase in invasiveness, enzymatic activity and differentiation in the clone showing low invasivity, low urokinase-type plasminogen activator levels and high differentiation. In contrast, in the clone showing high invasivity, high urokinase-type plasminogen activator levels and low differentiation it was found that: TPA was ineffective; retinoic acid induced a reduction of plasminogen activator but no modifications of invasiveness and differentiation; doxorubicin caused a decrease in invasiveness and plasminogen activator activity but no modification of morphological features. The different behaviour of the two clones thus could be related to the basal features of the clones. The results reported here indicate that in the presence of these drugs the associations between invasiveness and urokinase-type plasminogen activator activity and between invasiveness and differentiation are lost. Drug treatment therefore significantly affected the features of the clone characterized by low biological aggressiveness (high differentiation, low invasiveness), whereas the highly aggressive clone did not show a consistent response to drug treatment.
Melanoma Res 1994 Aug
PMID:Modification of invasion and differentiation in human melanoma cell clones. 795 Mar 60

Azelaic acid (AZA) has been used successfully in the treatment of lentigo maligna melanoma. Since it is generally accepted that the fibrinolytic potential of tumour cells is related to their malignant phenotype, it was the aim of this study to investigate the effect of AZA on the fibrinolytic potential of three different human melanoma cell lines (Bowes, GUBSB and MJZJ). Melanoma cells were incubated with AZA in doses ranging from 10(-2) M to 4 x 10(-2) M for 5, 8 and 24 h. The expression of tissue-type plasminogen activator (t-PA), urokinase-type PA (u-PA) and PA inhibitor-1 (PAI-1) in such treated cells was investigated by specific ELISAs on the protein level and by Northern blotting on the mRNA level. AZA caused a time and dose dependent decrease in the fibrinolytic potential of all three cell lines investigated by decreasing t-PA antigen in Bowes, by decreasing u-PA antigen in GUBSB and by increasing PAI-1 antigen in MJZJ cells, respectively. There was no significant difference between the viability of cells in control cultures and those treated with AZA. The effect of AZA on specific mRNA for t-PA in Bowes cells, u-PA in GUBSB and PAI-1 in MJZJ was consistent with its effect on the secretion of these fibrinolytic proteins by the respective cells. The results show that AZA decreases the fibrinolytic potential of the three human melanoma cell lines in vitro. This decrease may be operative in the mechanism by which AZA has been shown to affect malignant melanoma in vivo.
 ...
PMID:Azelaic acid decreases the fibrinolytic potential of cultured human melanoma cells in vitro. 863 47

A large body of evidence suggests a role for the proteolytic plasminogen activation system in invasion and metastatic spread of tumor cells including melanoma cells. Plasminogen activation by human melanoma cell lines and B16 mouse melanoma cell lines has been extensively studied. Apart from expression of urokinase-type plasminogen activator, melanoma cells differ from cells derived from other tumors in the abundant expression of tissue-type plasminogen activator. The possible role of both types of plasminogen activator in metastatic spread of melanoma cells is discussed. In recent years the localization of mRNAs and proteins of the plasminogen activation system and of related proteins in cutaneous melanocytic tumor progression has been well documented. A possible mechanism for migration of melanoma cells in vivo is suggested.
Melanoma Res 1996 Apr
PMID:The plasminogen activation system in melanoma cell lines and in melanocytic lesions. 879 Dec 64

Cutaneous melanoma is an invasive and early metastazising tumor. Melanoma cells detach from the primary tumor, penetrate the basement membrane, invade lymphatics and blood vessels, and form metastases. These processes all depend on coordinated expression and/or activation of proteolytic enzymes. In addition to aspartyl- and cysteineproteinases, serine proteinases including the plasminogen activator system (uPA, uPAR, tPA, PAI-1 and PAI-2) and matrix metalloproteinases (MMPs) with their tissue inhibitors (TIMPs) play an essential role in these processes. In addition, melanoma cells require specific adhesion molecules such as integrins and CD44 for interaction with other cells and components of the extracellular matrix (ECM); these are also involved in binding activated MMPs on the cell surface. In this review we discuss these functional aspects of melanoma progression.
 ...
PMID:[Role of matrix-degrading enzymes in melanoma progression]. 1220 62

Melanoma cells produce tissue plasminogen activator (t-PA) that plays an important role in tumor invasion and metastasis. The production of t-PA by normal human uveal melanocytes has not been reported previously. In order to explore this possibility, we studied the production of t-PA by cultured human uveal melanocytes and compared that with the production by cultured human uveal melanoma cells and epidermal melanocytes. Human adult uveal melanocytes were isolated and cultured from donor eyes. The cells were cultured in serum-free medium for 48 h and the conditioned medium then collected for the plasminogen activator (PA) activity assay. Free PA activity was tested in an amidolytic assay using a t-PA standard curve. PA type was identified by fibrinography and antihuman t-PA and urokinase plasminogen activator (u-PA) blocking antibodies. Free PA activity was found in the conditioned medium of normal melanocytes and melanoma cells. The predominant PA activity was t-PA. Normal uveal melanocytes produced more t-PA (3.23 +/- 0.73 IU/105 cells/24 h) than that of epidermal melanocytes (1.25 IU/105 cells/24 h) but much less than uveal melanoma cells (11.0 +/- 3.39 IU/105 cells/24 h). Western blot analysis revealed that most t-PA in conditioned media were one-chain t-PA with molecular weight of 69 kDa. Our study indicates that uveal melanocytes may contribute to the free t-PA activity previously found in aqueous humor and choroidal eye cup superfusions. Therefore, this function of uveal melanocytes may play a role in intraocular matrix remodeling, fibrinolysis and aqueous humor outflow.
 ...
PMID:Tissue plasminogen activator is released into cultured medium by cultured human uveal melanocytes. 1221 94

The demonstration that zinc-finger transcriptional repressors can control E-cadherin expression in epithelial cells has provided a new avenue of research in the field of epithelial-mesenchymal transition (EMT). One of these zinc-finger molecules is the transcription factor Snail, which controls gastrulation and neural crest EMT in different species. Additionally, Snail is involved in the development of malignant melanoma where a dramatic change in E-cadherin expression is an important early step for melanoma progression. For this study, a human cancer cDNA array was used which includes genes involved in cancer development and progression. Using the array we compared the gene expression pattern of the melanoma cell line Mel Im with a Mel Im cell clone stable transfected with antisense (as) SNAIL cDNA. We validated the significant differences of the expression of genes on mRNA level. Primarily, we observed changes in the expression of genes involved in EMT. Quantitative real-time polymerase chain reaction showed a down-regulation of MMP-2, EMMPRIN, SPARC, TIMP-1, t-PA, RhoA and Notch4 expression and a re-induction of E-cadherin expression in the as Snail cell clones. Furthermore, we measured the expression of integrin beta3, NM23b and RhoB. Additionally, we investigated whether the selected genes are influenced only through Snail or if E-cadherin can influence the expression of these genes. In summary, all examined genes which are influenced through Snail have a regulatory function in EMT processes as does Snail itself. The Snail target gene E-cadherin has no regulatory function with respect to the selected genes.
Melanoma Res 2005 Aug
PMID:Snail-regulated genes in malignant melanoma. 1603 10


1 2 Next >>