Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase C (PKC) activation was examined for its role in delta-opioid receptor down-regulation in the neuroblastoma X glioma hybrid cell line NG108-15. Incubation of NG108-15 cells for 2 hr at 37 degrees with up to 1 microM 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA), a phorbol ester that activates PKC, had no effect on opioid binding to membranes prepared from these cells. However, as little as 3 nM PMA incubated with an opioid agonist and NG108-15 cells potentiated the decrease and the rate of decrease of opioid binding, compared with agonist alone. Scatchard analysis of [3H][D-Ala2,D-Leu5]enkephalin (DADLE) binding revealed that NG108-15 cells incubated for 3 hr with 1 nM DADLE and 30 nM PMA displayed a > 50% reduction in the number of [3H]DADLE binding sites with no affinity change at the remaining sites, compared with cells treated with DADLE alone. The antagonist naloxone blocked both DADLE-induced and PMA-enhanced DADLE-induced down-regulation. The agonists morphine and cyclazocine, which alone were unable to induce delta receptor down-regulation, did so in the presence of PMA. The PKC inhibitor staurosporine and down-regulation of PKC by chronic PMA treatment blocked PMA potentiation of DADLE-induced down-regulation, but not "normal" DADLE-induced down-regulation. The enhancement of down-regulation by PMA was unaffected by either metabolic inhibitor or incubations at 20 degrees, conditions that blocked down-regulation by DADLE alone. NG108-15 cells incubated with [3H]DADLE and PMA retained more [3H]DADLE than cells incubated with [3H]DADLE alone, suggesting that PMA enhanced receptor internalization instead of merely inhibiting membrane binding. The diacylglycerol 1-oleoyl-2-acetyl-glycerol and bradykinin substituted for PMA but not carbachol, indicating that PKC activated physiologically may play a role in delta receptor down-regulation.
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PMID:Protein kinase C activation increases the rate and magnitude of agonist-induced delta-opioid receptor down-regulation in NG108-15 cells. 133 57

The role of protein kinase C in migration of tumor cells from spheroid cultures was investigated using parental rat glioma cells and their TPA resistant counterparts. These two lines differed in their PKC content as judged by the histone phosphorylation method. Also 4 days of treatment with IRA led to PKC down-regulation. Cells having a drastically decreased PKC level migrated better than those having a normal PKC content.
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PMID:The role of protein kinase C in migration of rat glioma cells from spheroid cultures. 156 92

The mechanisms by which lymphokine-activated killer (LAK) cells exert their cytotoxic effects are not well understood. This study demonstrates that phorbol ester pretreatment of a LAK cell-sensitive glioma cell line (SNB-19) induced a significant decrease in the susceptibility of cells to LAK cell-mediated lysis. This effect was produced by low concentrations of the tumor-promoting phorbol ester, phorbol-12,13-myristate acetate (PMA), and was reversible. Protein kinase C (PKC) inhibitors failed to block this phenomenon. No apparent alteration in the ability of LAK cells to bind to their targets was observed. Thus, PMA may have exerted its effects by a mechanism that does not require PKC, or these glioma cells may possess an isozyme of PKC which is insensitive to the inhibitors used in these studies.
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PMID:Effect of phorbol esters on the susceptibility of a glioma cell line to lymphokine-activated killer cell activity. 235 27

Protein kinase C (PKC), the major receptor for tumor-promoting phorbol esters, consists of a family of at least 12 distinct lipid-regulated enzymes. We examined the expression and regulation of PKC isoforms in C6-glioma and NG 108-15 hybrid cells. Western blot analysis indicated that both cell lines express four PKC isoforms, PKC alpha, PKC delta, PKC epsilon and PKC zeta. The expression of PKC alpha and PKC delta in C6-glioma cells was more abundant than NG 108-15 cells, however, PKC epsilon in NG 108-15 was more abundant than C6-glioma cells in which PKC epsilon was almost undetectable. Treatment of both cells with TPA for 10 min resulted in the translocation of PKC alpha, PKC delta and PKC epsilon to the membrane fraction. When the intact cells were treated with Ca(2+)-free, EGTA containing physiological saline solution, the membrane bound conventional PKC alpha (cPKC alpha) was greatly reduced and cytosolic cPKC alpha was only slightly increased. However, neither membrane bound nor cytosolic new PKC delta (nPKC delta), nPKC epsilon and atypical PKC zeta (aPKC zeta) was affected by extracellular Ca2+ depletion. In this condition, the translocation of cPKC alpha, nPKC delta and nPKC epsilon induced by TPA still occurred, however, that of cPKC alpha was reduced more than in the normal condition. After long-term treatment (17 h) with TPA, cPKC alpha, nPKC delta and nPKC epsilon were down-regulated both in the cytosol and membrane. The phenomena of cPKC alpha were confirmed by measuring the PKC activity with histone as the substrate. From in vitro endogenous phosphorylation studies, a 31 kDa substrate protein phosphorylation in C6 glioma cell membrane and 31 and 26 kDa proteins in NG 108-15 cell membrane were increased in the translocation but disappeared in the down-regulation of PKC.
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PMID:Differential expression of protein kinase C isoforms in glial and neuronal cells. Translocation and down-regulation of PKC isoforms in C6 glioma and NG 108-15 hybrid cells: effects of extracellular Ca(2+)-depletion. 749 43

Recent studies have suggested that the triphenylethylene antiestrogen tamoxifen inhibits the proliferation in vitro of a substantial percentage of cell lines derived from adult high-grade gliomas, potentially acting through inhibition of the second messenger protein kinase C. These findings have formed the impetus for clinical trials of this agent in adults with malignant gliomas. However, it has previously remained uncertain whether tamoxifen has a similar inhibitory effect on the proliferation of pediatric high-grade gliomas, and whether low-grade gliomas, which constitute the majority of glial neoplasms in children, are also inhibited by this agent. To address these issues, the present study examined the effect of tamoxifen on proliferation and viability in a series of low-passage cell lines derived both from low-grade and high-grade pediatric gliomas. This agent was tested in three malignant gliomas, two pilocytic astrocytomas, two non-pilocytic low-grade astrocytomas, 1 mixed glioma, and 1 oligodendroglioma. Tamoxifen produced a dose-dependent inhibition of proliferation in two of the three malignant glioma cell lines and in each of the low-grade glioma cell lines with a 50% effective dose of approximately 3 micrograms/ml (5.4 microM), which is comparable to the IC50 for inhibition of PKC activity by this agent. No significant cytotoxicity was encountered at this concentration. However, complete elimination of proliferation was achieved with a dose of 10 micrograms/ml (17.8 microM), which produced a direct cytotoxic effect. We conclude that tamoxifen inhibits proliferation of cell lines derived from both low-grade and high-grade pediatric glial tumors in vitro at concentrations that may be achievable clinically with high-dose oral therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The efficacy of tamoxifen as an antiproliferative agent in vitro for benign and malignant pediatric glial tumors. 757 61

Trapidil is a PDGF antagonist that can inhibit the proliferation of the PDGF-producing glioma cells, U251MG. As the mechanism of growth-regulation by trapidil remains unclear, we studied its effect on the growth of U251MG cells. We performed a cell cycle analysis and examined the intracellular transduction pathway and oncogene expression in serum-stimulated glioma cells with or without trapidil. After the serum starvation for 3 days, glioma cell proliferation was stimulated by the addition of serum. Cell cycle analysis showed that cell cycle perturbations induced by trapidil included a decreased transition rate from G0-G1 to S phase, suggesting that some metabolic event is required for progress through the G0-G1 phase and that this event is sensitive to trapidil. Internal signal transduction mechanisms are central in the molecular control of cell growth. One such regulator is the protein kinase C(PKC) system and the c-fos gene is likely to be a direct target of intracellular signal transduction pathways. Therefore, we hypothesize that the intracellular PKC activity and c-fos expression of the trapidil-treated cells are suppressed. We posit that trapidil affects the intracellular signal transduction pathway PKC activity and c-fos expression in cells stimulated with serum containing growth factors.
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PMID:The mechanism of growth-regulation of glioma cells by trapidil. 767 82

Correlation between translocation and down-regulation of conventional protein kinase C alpha (cPKC alpha) and new PKC delta (nPKC delta) induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) at different time courses (5 min, 30 min, 1 h, 3 h, 6 h, 10 h, 17 h, and 24 h) was studied in C6 glioma cells. From the dose-dependent translocations of these two isoforms by 10-min treatment with TPA (1, 3, 10, 30, 100, 300, and 1,000 nM), we found that cPKC alpha was translocated by 3-1,000 nM and nPKC delta was translocated by 10-1,000 nM TPA. Both isoforms were maximally translocated by 100-1,000 nM TPA, whereas 1 nM did not translocate these two isoforms. When the cells were treated with 1,000 nM TPA for 5 min to 17 h, the translocation of these two isoforms occurred rapidly after 5-min treatment and could be sustained for 1 h, whereas down-regulation occurred after 3-h treatment and almost complete down-regulation was observed after 17-h treatment. However, the extent of down-regulation of nPKC delta was greater than that of cPKC alpha at 3-, 6-, and 10-h treatment. Further studies by using different doses of TPA (100, 10, 3, and 1 nM) and extending the time to 24 h showed that cPKC alpha was more resistant to down-regulation. This conventional isoform was maintained at a translocation state even after long-term treatment with 3-100 nM TPA, and complete down-regulation was only shown after 1,000 nM treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential correlation between translocation and down-regulation of conventional and new protein kinase C isozymes in C6 glioma cells. 783 75

Protein kinase C (PKC) enzyme activity in a mouse glioma cell line G-26 and a human glioma cell line U-373 were compared at similar cell confluency in-vitro to establish if a G-26 in-vivo mouse model would be useful to examine the role of PKC inhibitors in controlling human glioma growth in-vivo. Original crude cytosolic and membrane PKC fractions of both mouse glioma G-26 and human glioma U-373 cells did not display significant PKC activity compared to partially purified PKC. Partial purification of mouse glioma G-26 and U-373 cytosolic and membrane fractions showed different cytosolic and membrane PKC activity profiles. Total PKC activity was higher (rho = 0.0001) in human glioma U-373 (7840 picomoles/mg/min) than in mouse glioma G-26 cells (2890 picomoles/mg/min). Thus, results from trials using nude mice human glioma xenografts may be more valid than those obtained from a G-26 in-vivo mouse model for studying the effects of therapeutic drugs on PKC isozymes.
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PMID:Heterogeneity of protein kinase C activity in human U-373 and G-26 mice glioma cells. 799 12

The effects of Ca2+ on the translocation of conventional and new protein kinase C isozymes in intact cells were studied by using C6 glioma cells as a model system. Two conditions which monitor intracellular Ca2+ were performed: one is extracellular Ca(2+)-depletion by treating the cells with physiological saline solution (PSS) without Ca2+ but containing 0.5 mM EGTA, the other is treating the cells with 1 microM ionomycin to induce Ca(2+)-influx. In addition, the TPA and endothelin-1 induced translocations of conventional and new PKC isozymes under these two conditions were also comparatively studied. When the intact cells were treated with Ca(2+)-free, EGTA containing PSS, the membrane-bound conventional PKC alpha (cPKC alpha) was greatly reduced and cytosolic cPKC alpha was slightly increased. However, neither membrane bound nor cytosolic new PKC delta (nPKC delta) was affected by extracellular Ca(2+)-depletion. On the other hand, when the cells were treated with 1 microM ionomycin, the translocation of cPKC alpha itself was observed while nPKC delta was not affected. In extracellular Ca(2+)-depletion, the translocation of cPKC alpha induced by 100 nM TPA still occurred although the extent of translocation was smaller than that induced by TPA under normal Ca2+ conditions; however, that induced by 30 nM ET-1 was blocked. After the cells were treated with 1 microM ionomycin, the translocation of cPKC alpha induced by 30 nM TPA was further increased compared to 1 microM ionomycin or 30 nM TPA alone, while that induced by ET-1 was only slightly further increased. All these results suggested that in intact cells, the activation of cPKC alpha was operated by both the intracellular Ca2+ level and diacylglycerol and that of nPKC delta was operated by diacylglycerol alone as predicted by their properties from purified enzyme or cDNA. In addition, the translocation of cPKC alpha induced by the natural activator ET-1 seemed to be more dependent on Ca2+ than TPA in intact cells.
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PMID:Effects of Ca2+ on the activation of conventional and new PKC isozymes and on TPA and endothelin-1 induced translocations of these isozymes in intact cells. 802 77

The parallel effects of simvastatin on cell cycle and PKC activity in rat C6 glioma cells were investigated. Simvastatin, 2.5 microM, for 24 h resulted in cell growth arrest in early G1 phase of the cell cycle and in a significant increase of total PKC activity (283 +/- 42 vs 470 +/- 61 pmoles/min/mg protein p = 0.002 for control cells and simvastatin-treated cells, respectively). The effect of simvastatin was fully prevented by mevalonate. A time dependent increase of PKC activity was observed in control exponentially free-growing C6 cells approaching confluency: a highly significant negative correlation (r = -0.91 p < 0.0001) between PKC activity and growth rate was calculated. PKC activity was high in cells arrested in G0 by serum starvation (0.4%). Following addition of complete medium (17.5% serum) the PKC activity progressively decreased and reached a minimum when cells traversed the G2/M phase, as determined by DNA analysis distribution. PKC activity dropped 30% in simvastatin-arrested early G1 cells; 44% in hydroxyurea-arrested cells at the G1/S boundary; and 73% in Colcemid mitosis-blocked cells. The results show that C6 glioma cell PKC activity is maximal in a G0 quiescent state and varies at different points of the cell cycle.
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PMID:PKC activity in rat C6 glioma cells: changes associated with cell cycle and simvastatin treatment. 817 95


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