UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conditioned media from two human malignant gliomas, C6 rat glioma, Walker 256 carcinosarcoma, and normal human glia were concentrated 50-fold to create a culture supernatant (SUP-C). The effect of SUP-C on rat brain capillary permeability was investigated by measuring the entry of 14C-aminoisobutyric acid (14C-AIB) by means of quantitative autoradiography. The SUP-C contained proteins with a molecular weight of 10 kD or greater. The SUP-C from all tumor cells markedly increased brain capillary permeability, indicating the presence of a permeability factor, whereas that from normal glial cells did not. Glioma cells produced more factor after incubation for 20 hours than 4 hours. The activity of capillary permeability factor in the SUP-C was inhibited by pretreatment of animals with BW755C (lipoxygenase inhibitor), but not with indomethacin (cyclo-oxygenase inhibitor). Pretreatment of animals with dexamethasone prior to intracerebral infusion of tumor SUP-C significantly reduced the factor-induced increase in capillary permeability. On the other hand, coincubating glioma cells with dexamethasone produced SUP-C with a permeability activity that was about one and a half times greater than that without dexamethasone. These results indicate that glucocorticoids produce their anti-edema effects by directly acting on capillary endothelial cells, possibly through the inhibition of phospholipase A2 activity, resulting in a decrease of lipoxygenase rather than cyclo-oxygenase products. The production of capillary permeability factor by tumor cells was not inhibited, but rather enhanced, by administration of glucocorticoids.
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PMID:Capillary permeability factor secreted by malignant brain tumor. Role in peritumoral brain edema and possible mechanism for anti-edema effect of glucocorticoids. 210 24

Tumor-promoting phorbol esters such as 4 beta-phorbol 12-myristate 13-acetate (PMA) have been shown to act synergistically with Ca2+ ionophores in cell activation, including stimulation of arachidonic acid metabolism. The effects of PMA on unstimulated and Ca2+ ionophore- or thrombin-stimulated PGI2 and platelet-activating factor (PAF) production in cultured bovine aortic endothelial cells (BAEC) and human umbilical vein endothelial cells (HUVEC) were investigated. Incubation of BAEC or HUVEC for 5-10 min with 100 nM PMA alone slightly increased basal PGI2 production. PGI2 production was rapidly stimulated in BAEC and HUVEC treated with the Ca2+ ionophore ionomycin. Preincubation of BAEC or HUVEC with 100 nM PMA for 5-10 min followed by ionomycin for up to 60 min enhanced PGI2 production up to 2.5-fold. Pretreatment with 100 nM PMA for 5 min also caused a 2-fold enhancement of thrombin-stimulated (1 U/ml) PGI2 production in HUVEC. The production of other prostaglandins, PGF2 alpha, PGE2, and PGD2, was also enhanced. In contrast, PMA had no effect on PGI2 synthesized directly from exogenous arachidonic acid or PGH2. The inactive phorbol ester 4 alpha-phorbol 12,13-didecanoate was without effect. Since the biosyntheses of both PGI2 and PAF share a common first step, the hydrolysis of their respective phospholipid precursors by phospholipase A2, we investigated whether PMA preincubation could also enhance PAF biosynthesis. Incubation of HUVEC with 100 nM PMA alone had a negligible effect on PAF production. However, thrombin-stimulated (1 U/ml) PAF production was enhanced 2.6-fold by preincubation with 100 nM PMA. The protein kinase C inhibitors H-7 and staurosporine ablated the enhancing effect of PMA on thrombin-stimulated PGI2 and PAF biosynthesis. These results demonstrate that PMA can significantly alter the production of PGI2 and PAF in vascular endothelial cells, and suggest that protein kinase C activation modulates phospholipase A2 activity in this cell type.
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PMID:Enhancement of thrombin- and ionomycin-stimulated prostacyclin and platelet-activating factor production in cultured endothelial cells by a tumor-promoting phorbol ester. 211 37

Prostaglandin E2 (PGE2) release from primary cultures of mouse epidermal cells was markedly stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), mezerein and 1-oleoyl-2-acetyl-glycerol but not by 4 alpha-phorbol-12,13-di-decanoate in low Ca2+ (50 microM) medium. TPA-evoked PGE2 release was inhibited by mepacrine, indomethacin and H-7 but not by HA1004. These findings suggest that TPA stimulates PGE2 release through activation of protein kinase C, phospholipase A2 and the cyclooxygenase pathway. Of the non-TPA type of tumor promoting agents, i.e. anthralin, chrysarobin, 7-bromomethylbenz[a]anthracene, benzoylperoxide, okadaic acid and palytoxin, only anthralin stimulated PGE2 release. Anthralin-evoked PGE2 release was not inhibited by H-7. In normal Ca2+ (1.8 mM) medium, PGE2 release increased markedly compared to the release in low Ca2+ medium. In normal Ca2+ medium, PGE2 release was stimulated by TPA, anthralin and okadaic acid but not by other tumor promoting agents. In mouse peritoneal macrophages, TPA, palytoxin and okadaic acid stimulated PGE2 release, but other tumor-promoting agents failed to stimulate it. These results suggest that skin tumor promoting agents are not necessarily effective stimulators of prostaglandin production either in macrophages or in epidermal cells, the target cells of skin tumor promotion.
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PMID:Differential effects of various skin tumor-promoting agents on prostaglandin E2 release from primary cultures of mouse epidermal cells. 211 11

The molecular mechanism of the glucocorticoid-induced inhibition of prostanoid synthesis was investigated in human monoblastoid U937 tumor cells and phorbol ester (TPA)-differentiated U937 cells. Prostanoid synthesis was inhibited in TPA-differentiated U937 cells by glucocorticoids such as dexamethasone and prednisolone, whereas aldosterone and progesterone showed no inhibitory effect. None of these methods had any influence on prostanoid secretion of undifferentiated U937 cells. Receptor binding studies revealed the presence of glucocorticoid receptors in both undifferentiated and TPA-differentiated U937 cells (Kp approximately 5 x 10(-9)M), however, the number of receptors per cell was increased 10-fold in TPA-differentiated U937 cells. Expression of lipocortin I and II as measured by Western blot analysis was not affected by dexamethasone. In TPA-differentiated cells, dexamethasone decreased the activities of two enzymes essential for prostanoid synthesis, cyclooxygenase and phospholipase A2, by 60-70% and 30%, respectively. Cells pretreated with the translation inhibitor cyclohexmide and dexamethasone showed similar cyclooxygenase and phospholipase A2 activities as cells treated with cycloheximide alone. Western blot analysis demonstrated that the significantly decreased cyclooxygenase activity correlated with an inhibited protein synthesis. In this human macrophage-like model glucocorticoids thus interfere at least at two levels with prostanoid synthesis by inhibiting the activities of phospholipase A2 as well as cyclooxygenase.
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PMID:Glucocorticoid-induced reduction of prostanoid synthesis in TPA-differentiated U937 cells is mainly due to a reduced cyclooxygenase activity. 211 86

The tumor-promoting phorbol ester 4 beta-phorbol 12-myristate 13-acetate (PMA) inhibited thrombin-stimulated arachidonic acid (AA) release in rabbit and human platelets. PMA was effective over the same concentration range that activates protein kinase C in intact rabbit platelets: IC50 vs thrombin = 0.5 nM, greater than 90% inhibition at 10 nM. Suppression of thrombin-stimulated AA release was evident within 5 min of pretreatment with 1 nM PMA. A non-tumor-promoting phorbol ester, 4-O-methyl PMA, showed a very weak ability to inhibit AA release. Thrombin-stimulated serotonin secretion was progressively inhibited by PMA pretreatment in platelets, while PMA was a stimulus for secretion at higher concentrations. 1-(5-Isoquinolinylsulfonyl)-2-methyl-piperazine (H-7), a selective inhibitor of protein kinase C, blocked PMA-induced inhibition of AA release. Furthermore, H-7 enhanced the effect of thrombin on AA release. PMA pretreatment reduced the inhibitory effect of thrombin on forskolin-stimulated cAMP accumulation, but had no effect on nonstimulated cAMP metabolism in the presence of thrombin. PMA did not inhibit AA release caused by A23187 or melittin. In digitonin-permeabilized platelets, thrombin plus guanosine 5'-(3-O-thio)triphosphate (GTP gamma S)-stimulated AA release, but not GTP gamma S- and AIF4(-)-stimulated AA release, was abolished by PMA pretreatment. These results suggest that activation of protein kinase C may exert negative feedback on the receptor-mediated activation of phospholipase A2. A possible uncoupling of thrombin receptor to GTP-binding protein leading to activation of phospholipase A2 by PMA pretreatment is discussed.
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PMID:Modes of inhibitory action of 4 beta-phorbol 12-myristate 13-acetate in thrombin-stimulated arachidonic acid release in intact and permeabilized platelets. 215 60

In order to delineate structural-functional relationships of the mast cell receptor for IgE (Fc epsilon RI) by molecular-genetic analysis, a transfectable cell must be identified which resembles mast cells except for being deficient in receptors. We have found that the well known murine mastocytoma P815 is suitable. These cells express no Fc epsilon RI, lack mRNA for the alpha and beta subunits of the receptor, but contain some mRNA for gamma chains. After transfection with the cDNA for each of the subunits, stable clones could be isolated which expressed several hundred thousand normal Fc epsilon RI and synthesized large amounts of mRNA for alpha, beta, and gamma, the last at 3-fold higher levels than in the untransfected cells. Aggregation of the transfected receptors led to opening of presumptive calcium channels and to activation of phospholipase C, phospholipase A2, and protein kinase C. The kinetics and other characteristics of the signals were similar to those observed after stimulation of the rat tumor mast cells from which the receptor genetic material had been derived but were smaller in magnitude. These weaker signals most likely result from an overall reduced reactivity exhibited by the P815 cells since stimulation by other ligands led to weaker or even no responses. The cells failed to degranulate after either receptor aggregation or reaction with ionophores with or without phorbol ester. Both the transfected and untransfected P815 cells express Fc receptors for IgG (Fc gamma RII) which, interestingly, independently triggered similar responses despite their apparently simpler subunit structure.
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PMID:Transmembrane signaling in P815 mastocytoma cells by transfected IgE receptors. 216 65

We have developed a new assay method for phospholipase A2 (EC 3.1.1.4.), towards ethanolamine plasmalogen using pyrenesulfonyl-labeled plasmenylethanolamine as the substrate. This procedure is sensitive to about 3 pmol/ml per min and is absolutely specific for plasmalogen. In this method, the product of phospholipase A2, pyrenesulfonyl-labeled lysoplasmalogen, is hydrolyzed to aldehyde and labeled glycerophosphoethanolamine with hydrochloric acid exposure, and after TLC separation, the pyrenesulfonyl-glycerophosphoethanolamine is quantitated spectrofluorometrically. The excitation and emission wave lengths were 340 and 376 nm, respectively. The activity of bovine brain homogenate was 44.1 +/- 6.47 pmol/min per mg protein (n = 3). Among bovine brain subcellular fractions, the distribution and specific activity of the enzymes were highest in cytosol (38.7 +/- 1.58% and 102.6 +/- 16.2 pmol/min per mg protein, n = 3). The activities of neural tumor cells, PC12 pheochromocytoma, Neuro2A and SKNSH neuroblastoma and U1242MG glioblastoma, were 34.4 +/- 6.83 (n = 5), 7.05 +/- 0.97 (n = 4), 5.25 +/- 1.69 (n = 5), and 9.68 +/- 1.35 (n = 4), pmol/min per mg protein (M +/- S.E.M.), respectively.
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PMID:Phospholipase A2 activities with a plasmalogen substrate in brain and in neural tumor cells: a sensitive and specific assay using pyrenesulfonyl-labeled plasmenylethanolamine. 217 64

We compared the antiproliferative efficacies of the natural human tumor necrosis factors alpha (nHuTNF-alpha) and beta (nHuTNF-beta). A phospholipase A2 inhibitor reduced the antitumor effects of both nHuTNF-alpha and nHuTNF-beta, but the inhibitory effect was more marked for nHuTNF-alpha than for nHuTNF-beta. Two other arachidonate metabolism pathways were also examined. A cyclo-oxygenase inhibitor moderately reduced nHuTNF-alpha-induced cell growth inhibition but did not affect nHuTNF-beta-induced growth inhibition, while a lipoxygenase inhibitor slightly reduced the antitumor effects of both types of nHuTNF. A third arachidonate metabolism pathway, cytochrome P450-dependent reductase inhibitor, did not affect nHuTNF-dependent growth inhibition. Exogenous cAMP and forskolin enhanced nHuTNF-alpha-induced growth inhibition but had no effect on nHuTNF-beta-induced growth inhibition. The stimulation of cancer cells by nHuTNF-alpha resulted in a significant elevation of intracellular cAMP concentrations, whereas nHuTNF-beta caused no such elevation. Additional studies demonstrated that combined nHuTNF-alpha and nHuTNF-beta (at similar unit concentrations, so that nHuTNF-beta was present at a molar concentration 1.4-fold greater than nHuTNF-alpha) showed an antitumor activity comparable to that of nHuTNF-alpha alone. These findings suggest the antiproliferative effect of nHuTNF-alpha to be both quantitatively and qualitatively distinguishable from that of nHuTNF-beta.
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PMID:A comparison of the antitumor effects of natural human tumor necrosis factors alpha and beta: the roles of arachidonic acid metabolism and intracellular cAMP. 217 97

Recent experimental evidence indicates that the c-Ha-ras (rasH) oncogene may be causally involved in the etiology and evolution of specific human neoplasms. In addition, cultured cells transformed by the rasH oncogene can induce both a tumorigenic and a metastatic phenotype when expressed in appropriate cultured cells. To begin to define the molecular and biochemical mechanism(s) by which the rasH oncogene induce their effects on expression of the transformed state we have employed a cloned rat embryo fibroblast (CREF) cell line. Transformation of CREF cells with wild-type 5 adenovirus (Wt) results in transformed cells which display anchorage-independence and an increased saturation density in monolayer culture, but are non-tumorigenic in both athymic nude mice and syngeneic Fischer rats. In contrast, when CREF cells are transformed with mutant type 5 adenoviruses, such as H5hrl, or the ElA transforming gene from hrl (0-4.5), tumors are induced in both nude mice and syngeneic rats. However, hrl (0-4.5)-transformed CREF cells are not metastatic following intravenous injection into the tail vein of syngeneic rats. Insertion of an activated T24 rasH oncogene or a wild-type v-rasH oncogene into CREF, wt-transformed CREF or hrl (0-4.5)-transformed CREF cells results in acquisition of a metastatic phenotype by these cells. A mutant v-rasH oncogene (mutant 116K), which is defective in GTP binding and the induction of transformation of NIH 3T3 cells, does not induce transformation in CREF cells, but it can progress wt-transformed CREF cells to a tumorigenic-non-metastatic state. Employing this model system which displays well-defined and stable stages in the tumor cell progression lineage, we have analyzed the potential role of changes in the phosphatidylinositol (PI) cycle and phospholipase A2 (PLA2) enzyme activity during progression to a tumorigenic and metastatic phenotype. An increase in PI cycle intermediates (primarily inositol triphosphate; IP3) were observed only in the wt-transformed and hrl (0-4.5)-transformed CREF cell lines transfected with the rasH oncogene. In the case of PLA2, all rasH-transformed CREF cell lines displayed increased activity. In contrast, CREF cells transformed only by Ad5 (Wt or hrl (0-4.5)) or the 116K v-rasH oncogene did not display increased PLA2 activity similar to that observed in rasH transfected cells. Since one important metabolite generated by PLA2 is arachidonic acid, which is converted into prostaglandins and leukotrienes by cyclooxygenase or lipooxygenase, respectively, the levels of prostaglandin E2 (PGE2) in the various cell lines were monitored.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of the Ha-ras (RasH) oncogene in mediating progression of the tumor cell phenotype (review). 219 86

The biosynthesis of platelet-activating factor (PAF-acether or 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) through the remodeling pathway was investigated at the subcellular level in two different cell lines. In human neutrophils, plasma membrane was isolated not only from granules, but also from internal membranes related to endoplasmic reticulum. Interestingly, the latter exhibited enhanced acetyltransferase upon neutrophil stimulation with ionophore A23187. A similar study was undertaken on the tumor strain Krebs-II cells. The enzyme acetyltransferase was found to be located only on an endoplasmic reticulum subfraction, whereas most alkylacyl-GPC, the source of PAF-precursor alkyl-lyso-GPC, was located in the plasma membrane inner leaflet. The topographical separation of enzyme and precursor emphasizes the central role of the intracellular phospholipase A2 in providing lyso-PAF to the acetyltransferase to form PAF-acether.
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PMID:Subcellular localization of phospholipids and enzymes involved in PAF-acether metabolism. 250 97

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