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

The induction of Hsp68 by heat shock (HS) and oxidative stress (OS) involves different pathways in C6 rat glioma cells. The pathways were analyzed by specific inhibitors of signal transduction cascades. Quercetin (inhibitor of PLA(2) and lipoxygenase) inhibited only the OS-induced but not the HS-induced expression of Hsp68. Preincubation with quinacrine (inhibitor of PLA(2)) before stress also suppressed the expression of Hsp68 only after oxidative stress. Moreover, another inhibitor of lipoxygenase (alpha-tocopherol) exclusively suppressed OS-induced Hsp68 expression. This different regulation was confirmed by exposing the cells to arachidonic acid (AA) during stress which strongly increased the induction of Hsp68 only after OS. PGE(2) (metabolite of cyclooxygenase) and indomethacin (inhibitor of cyclooxygenase) had no influence on Hsp68 expression in response to both stressors. The results suggest that the induction of Hsp68 by oxidative stress is mainly transmitted by the lipoxygenase pathway in C6 rat glioma cells.
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PMID:Induction of Hsp68 by oxidative stress involves the lipoxygenase pathway in C6 rat glioma cells. 1079 93

Several lines of evidence indicate that hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, c-Met, may play an important role in progression of human glioma. In this study, effects of HGF/SF on urokinase- type plasminogen activator (uPA)-mediated proteolysis network were examined in c-Met-positive human glioma cell lines. Treatment of the glioma cells with various concentrations of HGF/SF resulted in an enhanced secretion of uPA proteins accompanying increased transcription of uPA mRNA in a dose dependent fashion. The levels of uPA receptor (uPAR) mRNAs were also elevated simultaneously upon HGF/SF stimulation, and the cell-surface associated uPA activity was also elevated by the treatment. Since concomitant expression of HGF and its receptor c-Met are frequently observed in malignant gliomas, these results suggest that HGF/SF participates in invasive process of malignant glioma cells not only by its motility-stimulating activity but also through enhanced degradation of the extracellular matrix induced by autocrine activation of uPA proteolysis network.
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PMID:Simultaneous up-regulation of urokinase-type plasminogen activator (uPA) and uPA receptor by hepatocyte growth factor/scatter factor in human glioma cells. 1108 86

Cell contact with the extracellular matrix component, hyaluronan, plays a pivotal role in glioma cell invasion and proliferation. Although it is well established that glioma cells can bind hyaluronan to their surface via the expression of CD44, the cellular responses following ligand-receptor interaction remain poorly understood. Given that a large proportion of human high grade gliomas over express the epidermal growth factor receptor (EGFR) and ErbB2, this study aimed to investigate whether an interaction exists between CD44 and these receptor tyrosine kinases. Here we present evidence that CD44 co-immunoprecipitates with EGFR and ErbB2 in the glioma cell lines U87MG and SMA560. Hyaluronan treatment mediated the rapid and transient phosphorylation of extracellular signal regulated kinases 1 and 2 (ERK1 and ERK2) in glioma cell lines. This response to hyaluronan was augmented by the co-expression of EGFR. EGFR also differentially modified the hyaluronan induced expression of a number of genes associated with cellular invasion and proliferation. Northern blot analysis demonstrated that genes encoding urokinase type plasminogen activator (uPA), urokinase type plasminogen activator receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinases (TIMP-1) and c- myc were up-regulated in response to hyaluronan. Furthermore, zymographic analysis revealed increased levels of uPA in the conditioned medium of hyaluronan stimulated cells. These results indicate a novel functional relationship between CD44 and EGFR in glioma cell lines. The capacity of CD44 to form stable complexes with receptor tyrosine kinases may provide a versatile system for the regulation of cellular invasion and proliferation that allows hyaluronan to activate signal transduction pathways and modulate gene expression via an EGFR-dependent manner. These findings provide new insights into the mode by which hyaluronan regulates the malignant phenotype and also suggest a role for EGFR-CD44 interactions in glial tumorigenesis.
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PMID:EGF receptor modifies cellular responses to hyaluronan in glioblastoma cell lines. 1209 35

The blood-brain barrier (BBB) was modelled in this study using ECV304 cells in co-culture with rat C6 glioma cells, which resulted in elevated transendothelial electrical resistance (TEER). The inflammatory mediator bradykinin (1 microM) was studied and found to induce a fall in TEER; the link between this change and intracellular free calcium concentration ([Ca(2+)](i)) was then examined. 1 microM bradykinin produced a peak-plateau increase in [Ca(2+)](i). The peak showed desensitization and was dose dependent (over 0.1 nM to 1 microM). The [Ca(2+)](i) increase was blocked by the B(2) antagonist HOE 140 (1 microM) without effect from a B(1) agonist and antagonist. The plateau response was abolished in Ca(2+)-free solution containing 2 mM EDTA, and also by the Ca(2+) channel blockers lanthanum, La(3+) (10 microM), and SKF 96365 (100 microM). The store Ca(2+)ATPase inhibitor thapsigargin (1 microM) abolished the peak response. The putative phospholipase C inhibitors, U73122 (20 microM) and ETH-18-OCH(3) (100 microM), unexpectedly increased [Ca(2+)](i); after their application, bradykinin was ineffective. Agents without effect on Ca(2+) responses to bradykinin included the phospholipase A(2) (PLA(2)) inhibitor aristolochic acid (0.5 mM), cyclooxygenase inhibitor indomethacin (100 microM), 5-lipoxygenase inhibitor nordihydroguaiaretic acid, NDGA (100 microM), calphostin C (0.5 microM), L-NAME (1 mM) and nifedipine (10 microM). The fall in TEER from bradykinin was blocked by HOE 140, U73122 and thapsigargin combined with La(3+), and also by aristolochic acid and NDGA, but not indomethacin, calphostin C or L-NAME. U73122 increased TEER while ETH-18-OCH(3) reduced it. Thus bradykinin reduced TEER through B(2) receptor-linked release of Ca(2+) from thapsigargin-sensitive stores, leading to activation of PLA(2) and metabolism of arachidonic acid by 5-lipoxygenase.
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PMID:Bradykinin increases permeability by calcium and 5-lipoxygenase in the ECV304/C6 cell culture model of the blood-brain barrier. 1238 49

Baicalein is a flavonoid derived from the Scutellaria root. In investigations of the inhibitors of prostaglandin synthesis in C6 rat glioma cells, we found that baicalein had a potent inhibitory activity on prostaglandin synthesis induced by either histamine or A23187, a Ca(2+) ionophore. Baicalein inhibited histamine- or A23187-induced phosphorylation of p42/p44 extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK), which causes the phosphorylation of cytosolic phospholipase A(2) (PLA(2)). Baicalein also inhibited the phosphorylation of MAPK kinase-1 (MEK-1) induced by histamine or A23187 in the cells. To examine the site of action of baicalein, MEK-1 and Raf-1 were prepared by immunoprecipitation with anti-MEK-1 and anti-Raf-1 antibodies, respectively. Baicalein inhibited the phosphorylation of exogenous MEK-1 by Raf-1 under cell-free conditions, while it did not change the phosphorylation of exogenous p42 MAPK by MEK-1. These results imply that baicalein inhibits the ERK/MAPK cascade, acting on the phosphorylation of MEK-1 by Raf-1.
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PMID:Baicalein inhibits Raf-1-mediated phosphorylation of MEK-1 in C6 rat glioma cells. 1256 9

The metastatic spread of cancer is a complex process that involves the combination of different cellular actions including cell adhesion to the extracellular matrix (ECM), breakdown of the ECM by specific matrix-degrading proteinases, and active cell locomotion. Contortrostatin (CN), a homodimeric snake venom disintegrin, has previously been demonstrated to be effective in blocking vitronectin/fibronectin-dependent adhesion and invasion of T98G human glioblastoma cells through Matrigel using in vitro studies. However, it is not known at what step of the invasion process CN exerts its inhibitory effect. In the present report, CN is shown to decrease invasion of various glioma cell lines through Matrigel affecting neither cell adhesion, nor cell viability. While CN had no effect on cell binding to laminin and type IV collagen, it blocked adhesion of alphav beta3-positive, but not alphav beta3-negative cells, to vitronectin and fibronectin. Furthermore, members of the matrix metalloproteinase (MMP) family and their physiological inhibitors, and of the plasminogen activator (PA)/plasmin system were demonstrated not to be involved in CN-induced loss of glioma cell invasiveness. Instead, CN inhibited active locomotion of cells on Matrigel. These data suggest that CN-mediated inhibition of glioma cell invasion through Matrigel is a direct result of impaired cell motility. Moreover, use of several glioma cell lines and integrin antibodies strongly indicates the versatility of CN in inhibiting the invasion process based on the ability of CN to interact with different integrins, including alphav beta3, alphav beta5, and alpha5beta1.
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PMID:Functional effect of contortrostatin, a snake venom disintegrin, on human glioma cell invasion in vitro. 1288 Oct 36

There has been increasing interest in attempts to harness the body's normal inflammatory response mediated through the eicosanoid pathway to treat tumors. Accumulating data indicate that the growth of several different cancers is modulated by a group of pro-inflammatory bioactive lipids, the best known of which are the eicosanoids. Eicosanoid pathway constituents modulate cell function in several important ways, and an agent that activates PLA(2) and up-regulates LTB(4) levels could be expected to be an effective cytotoxic tumor agent, especially if it stimulated NK cells. PLAP is a 28-kDa polypeptide that is a member of the WD-repeat protein, G-protein-transducin superfamily. The pro-inflammatory properties of PLAP have been elucidated using a number of different approaches. PLAP has been found in inflamed tissues and synovial fluid from patients with rheumatoid arthritis. Based on knowledge of PLAP as a pro-inflammatory agent, its capacity to modulate the immune response and the role of the inflammatory and immune responses in immune surveillance, the role of PLAP in cancer therapy was explored. Significant tumor regression was observed 72 hours following a single treatment with PLAP in an animal air pouch model of glioma. PEG-PLAP treatment increased the life expectancy of animals with Lewis lung cancer, and in preliminary studies in MTVL breast tumors in mice, PLAP treatment resulted in a similar increase in life expectancy. These findings suggest that PLAP holds promise as a potential therapy for cancer, and warrants further study.
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PMID:Phospholipase A2 activating protein induces tumor regression. 1561 58

Polysorbate 80 (Tween 80) has been widely used as an emulsifier with excellent effects in nanoparticles technology for biomedical applications. This work was thus triggered to synthesize poly(lactide)/Tween 80 copolymers with various copolymer blend ratio, which were synthesized by ring-opening polymerization and characterized by 1H NMR and TGA. Nanoparticles of poly(lactide)/Tween 80 copolymers were prepared by the dialysis method without surfactants/emulsifiers involved. Paclitaxel was chosen as a prototype anticancer drug due to its excellent therapeutic effects against a wide spectrum of cancers. The drug-loaded nanoparticles of poly(lactide)/Tween 80 copolymers were then characterized by various state-of-the-art techniques, including laser light scattering for particles size and size distribution, field emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) for surface morphology; laser Doppler anemometry for zeta potential; differential scanning calorimetry (DSC) for the physical status of the drug encapsulated in the polymeric matrix; X-ray photoelectron spectrometer (XPS) for surface chemistry; high performance liquid chromatography (HPLC) for drug encapsulation efficiency; and in vitro drug release kinetics. HT-29 cells and Glioma C6 cells were used as an in vitro model of the GI barrier for oral chemotherapy and a brain cancer model to evaluate in vitro cytotoxicity of the paclitaxel-loaded nanoparticles. The viability of C6 cells was decreased from 37.4 +/- 4.0% for poly(D,L-lactide-co-glycolic acid) (PLGA) nanoparticles to 17.8 +/- 4.2% for PLA-Tween 80-10 and 12.0 +/- 5.4% for PLA-Tween 80-20 copolymer nanoparticles, which was comparable with that for Taxol at the same 50 microg/mL drug concentration.
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PMID:In vitro investigation on poly(lactide)-Tween 80 copolymer nanoparticles fabricated by dialysis method for chemotherapy. 1660 31

In a previous report, the recombinant kringle domain (UK1) of the urokinase type plasminogen activator (uPA) showed antiangiogenic activity. Here, we investigated in vivo antitumor effects of the UK1 of human uPA employing a brain tumor model. The systemic administration of UK1 purified from pichia expression (10 and 50 mg/kg/day intraperitoneally for 25 days) led to suppress the growth of a U87 human glioma xenograft, implanted into the brains of male BALB/cSlc nude mice, by 35% and 80%, respectively. In the immunohistochemical analysis, the tumors treated with UK1 showed decreased vascularity and expression of angiogenesis-related factors including vascular endothelial growth factor (VEGF), angiogenin, alpha-smooth muscle actin, von Willebrand's factor, and CD31 (PECAM-1 [Platelet endothelial cell adhesion molecule-1]), and increased apoptosis. UKl inhibited the in vitro proliferation and tube formation of VEGF-stimulated endothelial cells but not the proliferation of glioma cells. These results suggest that UK1 inhibits the malignant glioma growth by suppression of angiogenesis.
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PMID:The recombinant kringle domain of urokinase plasminogen activator inhibits in vivo malignant glioma growth. 1723 42

The duration of cisplatin release from most of the drug delivery devices seemed to be shorter than 14 days except large microparticles. The objective of this study was to fabricate and characterize cisplatin-loaded PLA microparticles, PLA/PLGA (30/70) composite microparticles, and fibers as formulations for long-term sustained delivery of cisplatin to treat C6 glioma in vitro by electrospray and electrospinning techniques. Cisplatin-loaded biodegradable microparticles with particle size of around 5 microm and fiber fabrics with diameter of 0.5-1.7 microm were obtained using electrospray and electrospinning techniques. Encapsulation efficiency and in vitro release of formulations were measured by ICP-OES. The encapsulation efficiency for different samples of microparticles was approximately from 33% to 72% and the fiber fabrics had encapsulation efficiency greater than 90%. Cisplatin-loaded microparticles showed typical characteristics of cisplatin release profile: a large initial burst followed by a sustained slow release of 35 days. The composite PLA/PLGA (30/70) microparticles could reduce the initial burst release of cisplatin because of their core-shell structures. In contrast, more than 75 days sustained release could be achieved by fiber fabric formulations without large initial burst. MTT assay was used to quantify the cytotoxicity of different formulations against C6 glioma cells. Microparticle formulations had slightly higher cytotoxicity than free drug. In contrast, the cytotoxicity of fiber fabrics formulation was around 4 times higher than of the free drug based on the actual amount of drug released. The microparticle and fiber fabric formulations presented may be promising for the sustained delivery of cisplatin to eliminate the undesired side effects caused by direct injection of cisplatin solution in systemic administration.
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PMID:Biodegradable microparticles and fiber fabrics for sustained delivery of cisplatin to treat C6 glioma in vitro. 1789 69


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