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)

Gliomas take a number of different genetic routes in the progression to glioblastoma multiforme, a highly invasive variant that is mostly unresponsive to current therapies. Gliomas express elevated levels of matrix metalloproteinases (MMPs), which have been implicated in the control of proliferation and invasion as well as neovascularization. Progressive loss of LGI1 expression has been associated with the development of high grade gliomas. We have shown previously that the forced re-expression of LGI1 in different glioma cells inhibits proliferation, invasiveness, and anchorage-independent growth in cells null for its expression. Here, using Affymetrix gene chip analysis, we show that reexpression of LGI1 in T98G cells results in the down-regulation of several MMP genes, in particular MMP1 and MMP3. LGI1 expression also results in the inhibition of ERK1/2 phosphorylation but not p38 phosphorylation. Inhibition of the MAPK pathway using the pharmacological inhibitors PD98059, U0126, and SB203580 in T98G LGI1-null cells inhibits MMP1 and MMP3 production in an ERK1/2-dependent manner. Treatment of LGI1-expressing cells with phorbol myristate acetate prevents the inhibition of MMP1/3 and restores invasiveness and ERK1/2 phosphorylation, suggesting that LGI1 acts through the ERK/MAPK pathway. Furthermore, LGI1 expression promotes phosphorylation of AKT, which leads to phosphorylation of Raf1(Ser-259), an event shown previously to negatively regulate ERK1/2 signaling. These data suggest that LGI1 plays a major role in suppressing the production of MMP1/3 through the phosphatidylinositol 3-kinase/ERK pathway. Loss of LGI1 expression, therefore, may be an important event in the progression of gliomas that leads to a more invasive phenotype in these cells.
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PMID:LGI1, a putative tumor metastasis suppressor gene, controls in vitro invasiveness and expression of matrix metalloproteinases in glioma cells through the ERK1/2 pathway. 1504 12

Here we characterize the intracellular effectors of the antiproliferative activity of somatostatin in glioma cell lines and post-surgical specimens. The responsiveness to somatostatin correlated with the expression of the phosphotyrosine phosphatase DEP-1/PTPeta, identified in C6 and U87MG cells, in which somatostatin inhibited cell growth. The expression of a dominant negative mutant of DEP-1/PTPeta in C6 cells abolished somatostatin effects, confirming the involvement of this phosphotyrosine phosphatase in such effects. Somatostatin treatment increased the activity of DEP-1/PTPeta and inhibited ERK1/2 activation. Conversely, basic fibroblast growth factor-dependent MEK phosphorylation was not affected, suggesting a direct effect on ERK1/2. In vitro experiments showed that PTPeta was able to interact and dephosphorylate ERK1/2 activated by basic fibroblast growth factor. Furthermore, by transfecting PTPeta in the somatostatin-unresponsive, DEP-1/PTPeta-deficient U373MG cells, the somatostatin-dependent control of cell proliferation was recovered. Finally we evaluated the requirement for DEP-1/PTPeta in somatostatin inhibition of cell proliferation in post-surgical specimens derived from different grade human gliomas. Although all of the glioma analyzed expressed somatostatin receptor mRNA, DEP-1/PTPeta expression was limited to 8 of 22 of the tumors. Culturing seven gliomas, a correlation between the expression of DEP-1/PTPeta and the somatostatin antiproliferative effects was identified. In conclusion we propose that the expression and activation of DEP-1/PTPeta is required for somatostatin inhibition of glioma proliferation.
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PMID:The expression of the phosphotyrosine phosphatase DEP-1/PTPeta dictates the responsivity of glioma cells to somatostatin inhibition of cell proliferation. 1512 17

We examined the impact of purified bacterially synthesized GST-MDA-7 (IL-24) and ionizing radiation on the proliferation and survival of nonestablished human glioblastoma multiforme (GBM) cells. Glioma cell types expressing mutated PTEN and p53 molecules, activated ERBB1VIII, overexpressing wild type ERBB1 or without receptor overexpression were selected. In MTT assays, GST-MDA-7 caused a dose-dependent reduction in the proliferation of nonestablished glioma cells; however only at higher concentrations did GST-MDA-7 reduce cell viability. The anti-proliferative and cytotoxic effects of GST-MDA-7 were enhanced by radiation in a greater than additive fashion that correlated with JNK1/2/3 activation. The reduction in cell growth and enhancement in cell killing by the combination of GST-MDA-7 and radiation were blocked by an ROS scavenger, N-acetyl cysteine (NAC), a JNK1/2/3 inhibitor SP600125, a pan-caspase inhibitor (zVAD) and by an inhibitor of caspase 9 (LEHD), but not by an inhibitor of caspase 8 (IETD). Low concentrations of either GST-MDA-7 or radiation reduced clonogenic survival, however colony formation ability was significantly further decreased when the two treatments were combined, which was also blocked by inhibition of caspase 9 function. In general agreement with activation of the intrinsic caspase pathway, cell death correlated with reduced BCL-XL expression and with increased levels of the pro-apoptotic proteins BAD and BAX. Inhibition of caspase 9 after combination treatment blunted neither JNK1/2/3 activation nor the enhanced expression of BAD and BAX, but did block caspase 3 cleavage, reduced expression of BCL-XL and inhibition of ERK1/2 activity. In contrast, incubation with NAC blocked JNK1/2/3 activation and cell killing, but not the increases in BAD and BAX expression. These findings argue that after combination treatment JNK1/2/3 activation is a primary pro-apoptotic event and loss of BCL-XL expression and ERK1/2 activity are secondary caspase-dependent processes. This data also argues that GST- MDA-7 induces two parallel pro-apoptotic pathways via ROS-dependent and -independent mechanisms. Infection of primary human astrocytes with a recombinant adenovirus to express MDA-7, Ad.mda-7, but not infection with either Ad.cmv or Ad.mda-7SP- lacking MDA-7 secretion, resulted in the suppression of GBM cell colony formation in soft agar overlay assays, an effect that was enhanced in a greater than additive fashion by radiation. Collectively, our findings demonstrate that MDA-7 reduces proliferation and enhances the radiosensitivity of nonestablished human GBM cells in vitro, and when grown in 3 dimensions, and that sensitization occurs independently of basal EGFR/ERK1/2/AKT activity or the functions of PTEN and p53.
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PMID:MDA-7 regulates cell growth and radiosensitivity in vitro of primary (non-established) human glioma cells. 1532 89

Effect of Mao-Bushi-Saishin-to (Ma-Huang-Fu-Zi-Xi-Xin-Tang: MBS) on prostaglandin E(2) (PGE(2)) production was investigated using C6 rat glioma cells. Mao or Saishin inhibited histamine-induced PGE(2) production while MBS slightly decreased and Bushi increased it. MBS and Mao inhibited and Bushi enhanced A23187-induced PGE(2) production while Saishin had no effect. Concomitantly, Mao inhibted, but Bushi fascilitated, histamine- and A23187-induced phosphorylation of extracellular signal-regulated kinase (ERK)1/2. Treatment of MBS, Mao and also Saishin increased cAMP content. From these results, MBS inhibit PGE(2) production in C6 cells, mainly due to Mao but also due to Saishin at least in part, and the counteraction of Bushi. The former effect is mediated by formation of cAMP and resulting inhibition of ERK1/2-phosphorylation.
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PMID:Inhibitory effect of Mao-Bushi-Saishin-to on prostaglandin E2 synthesis in C6 rat glioma cells. 1525 55

Amplification of the epidermal growth factor receptor (EGFR) or expression of its constitutively activated mutant, DeltaEGFR(2-7), in association with the inactivation of the INK4a/Arf gene locus is a frequent alteration in human glioblastoma. The notion of a cooperative effect between these two alterations has been demonstrated in respective mouse brain tumor models including our own. Here, we investigated underlying molecular mechanisms in early passage cortical astrocytes deficient for p16(INK4a)/p19(Arf) or p53, respectively, with or without ectopic expression of DeltaEGFR(2-7). Targeting these cells with the specific EGFR inhibitor tyrphostin AG1478 revealed that phosphorylation of ERK was only abrogated in the presence of an intact INK4a/Arf gene locus. The sensitivity to inhibit ERK phosphorylation was independent of ectopic expression of DeltaEGFR(2-7) and independent of the TP53 status. This resistance to downregulate the MAPK pathway in the absence of INK4a/Arf was confirmed in cell lines derived from our mouse glioma models with the respective initial genetic alterations. Thus, deletion of INK4a/Arf appears to keep ERK in its active, phosphorylated state insensitive to an upstream inhibitor specifically targeting EGFR/DeltaEGFR(2-7). This resistance may contribute to the cooperative tumorigenic effect selected for in human glioblastoma that may be of crucial clinical relevance for treatments specifically targeting EGFR/DeltaEGFR(2-7) in glioblastoma patients.
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PMID:INK4a/Arf is required for suppression of EGFR/DeltaEGFR(2-7)-dependent ERK activation in mouse astrocytes and glioma. 1527 38

Gliomas, in particular glioblastoma multiforme or grade IV astrocytoma, are the most frequent class of malignant primary brain tumours and one of the most aggressive forms of cancer. Current therapeutic strategies for the treatment of glioblastoma multiforme are usually ineffective or just palliative. During the last few years, several studies have shown that cannabinoids-the active components of the plant Cannabis sativa and their derivatives--slow the growth of different types of tumours, including gliomas, in laboratory animals. Cannabinoids induce apoptosis of glioma cells in culture via sustained ceramide accumulation, extracellular signal-regulated kinase activation and Akt inhibition. In addition, cannabinoid treatment inhibits angiogenesis of gliomas in vivo. Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death. These and other findings reviewed here might set the basis for a potential use of cannabinoids in the management of gliomas.
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PMID:Hypothesis: cannabinoid therapy for the treatment of gliomas? 1527 20

Both lead (Pb) and lipopolysaccharide (LPS) damage nervous system, partly, by the induction of tumor necrosis factor-alpha (TNF-alpha) in glia origin. In this study, we examined the Pb- and LPS-triggered signal leading to TNF-alpha expression in a glioma cell line, U-373MG. Both Pb and LPS increased the phosphorylation of p42/44 mitogen-activated protein kinase (MAPK), which depended on the activation of MAPK kinase (MEK) and protein kinase C (PKC). Selective p42/44 MAPK inhibitor could reduce the Pb- and LPS-triggered TNF-alpha expression in U-373MG cells. Suppressing PKC by chelerythrine chloride completely diminished the Pb- and LPS-induced TNF-alpha expression in glial cells in the mouse brain. Thus, our results indicated that PKC-MEK-p42/44 MAPK is a common signaling pathway for Pb- and LPS-induced TNF-alpha expression in glial cells.
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PMID:Regulation of tumor necrosis factor-alpha in glioma cells by lead and lipopolysaccharide: involvement of common signaling pathway. 1530 94

Regulators of G-protein signaling (RGS) proteins, by their action on Galpha(i/o) proteins, may enhance receptor-effector signaling by physical or kinetic scaffolding mechanisms. However, more than 30 mammalian proteins with RGS activity have been identified so it is difficult to determine which RGS protein is most relevant to a particular receptor system and in any particular cell. To avoid this problem, one approach is to examine agonist-stimulated second messenger signaling in cells expressing Galpha proteins that are insensitive to the GTPase accelerating property of all RGS proteins. This article describes protocols for the preparation and analysis of C6 rat glioma cells stably expressing RGS- and pertussis toxin-insensitive Galpha subunits; pertussis toxin treatment uncouples endogenous Galpha(i/o) proteins and allows for the determination of the expressed RGS-insensitive Galpha activity. Methods to determine signaling at the level of adenylyl cyclase, the extracellular signal-regulated kinase (ERK1/2) mitogen-activated protein kinase pathway, and intracellular Ca2+ levels are described. As a typical G-protein-coupled receptor, we have used the micro-opioid receptor expressed in C6 cells together with RGS-insensitive Galpha(o). In these cells, agonist inhibition of adenylyl cyclase and stimulation of ERK1/2 phosphorylation were enhanced markedly. In contrast, increases in intracellular calcium were less affected. The altered signaling in cells expressing RGS-insensitive Galpha(o) subunits allows for determination of the role of endogenous RGS proteins to limit and/or direct signaling.
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PMID:Assays for G-protein-coupled receptor signaling using RGS-insensitive Galpha subunits. 1531 65

Signal regulatory protein (SIRP) alpha1 is a membrane glycoprotein and a member of the SIRP receptor family. These transmembrane receptors have been shown to exert negative effects on signal transduction by receptor tyrosine kinases via immunoreceptor tyrosine-based inhibitory motifs in the carboxyl domain. Previous work has demonstrated that SIRPs negatively regulate many signaling pathways leading to reduction in tumor migration, survival, and cell transformation. Thus, modulation of SIRP expression levels or activity could be of great significance in the field of cancer therapy. The aim of the present study was to determine the factors that regulate levels of SIRPalpha1 in human glioblastoma cells that frequently overexpress the epidermal growth factor receptor (EGFR) because SIRPs have been shown to negatively regulate EGFR signaling. Northern blot analysis and immunoprecipitation assays showed variable expression levels of endogenous SIRPalpha transcripts in nine well-characterized glioblastoma cell lines. We examined SIRPalpha1 regulation in U87MG and U373MG cells in comparison with clonal derivatives that express a truncated form of erbB2, which negatively regulates EGFR signaling by inducing the formation of nonfunctional heterodimeric complexes. Mutant erbB2-expressing cells contained more SIRPalpha1 mRNA when compared with the parental cells in presence or absence of serum. Similarly, immunoprecipitation assays showed increased SIRPalpha1 protein levels in erbB-inhibited cells when compared with parental cells. Messenger RNA stability assays revealed that the increased mRNA levels in EGFR-inhibited cells were due to an induction of transcription. Consistent with this finding, expression of the erbB2 mutant receptor up-regulated SIRPalpha1 promoter activity in all cell lines tested. Interestingly, pharmacological inhibition of the kinase activities of EGFR, erbB2, and src and activation of mitogen-activated protein kinase, but not phosphatidylinositol 3'-kinase, significantly up-regulated SIRPalpha1 promoter activity. Based on these observations, we hypothesize that down-modulation of EGFR signaling leads to transcriptional up-regulation of the inhibitory SIRPalpha1 gene. These data may be important in the application of erbB-inhibitory strategies and for design of therapies for the treatment of glial tumors and other epithelial malignancies.
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PMID:Transcriptional regulation of signal regulatory protein alpha1 inhibitory receptors by epidermal growth factor receptor signaling. 1537 53

Brain ischemia brings about hypoxic insults. Hypoxia is one of the major pathological factors inducing neuronal injury and central nervous system infection. We studied the involvement of mitogen-activated protein (MAP) kinase in hypoxia-induced apoptosis using cobalt chloride in C6 glioma cells. In vitro cytotoxicity of cobalt chloride was tested by MTT assay. Its IC(50) value was 400 microM. The DNA fragment became evident after incubation of the cells with 300 microM cobalt chloride for 24 h. We also evidenced nuclear cleavage with morphological changes of the cells undergoing apoptosis with electron microscopy. Next, we examined the signal pathway of cobalt chloride-induced apoptosis in C6 cells. The activation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2) started to increase at 1 h and was activated further at 6 h after treatment of 400 M cobalt chloride. In addition, pretreatment of PD98059 inhibited cobalt chloride-induced apoptotic cell morphology in Electron Microscopy. These results suggest that cobalt chloride is able to induce the apoptotic activity in C6 glioma cells, and its apoptotic mechanism may be associated with signal transduction via MAP kinase (ERK 1/2).
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PMID:Cobalt chloride-induced apoptosis and extracellular signal-regulated protein kinase 1/2 activation in rat C6 glioma cells. 1546 37


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