Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies show that thiazolinediones (TZDs), agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma), induce apoptosis in glioma and glioblastoma cells. Here we compared the effects of troglitazone (Trog), a TZD with low affinity for binding to PPARgamma but with potent metabolic effects, on survival and metabolism in GL261 glioma cells versus primary astrocytes. Trog dose-dependently induced cell death in GL261 cells (with over 90% death at 30 microM) but did not cause any toxicity in astrocytes at the same doses. Measurements of glucose and lactate levels after incubation with Trog (30 microM) indicated an overall increase of glucose consumption and lactate production in both cell types. In astrocytes the ratio of lactate produced to glucose utilized was not significantly altered by Trog, while in glioma cells this ratio was decreased by about 40%. Trog dose-dependently reduced mitochondrial membrane potential (DeltaPsi(m)) in both cell types; and the loss of DeltaPsi(m) was greater in the tumor cells (90% loss at 20 microM) than in astrocytes (70% loss at 20 microM). These results suggest that differences in metabolic responses could contribute to the selective resistance of astrocytes to cytotoxic effects of Trog. TZDs such as Trog should therefore be considered for testing in treatment of gliomas.
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PMID:Differential effects of PPARgamma agonists on the metabolic properties of gliomas and astrocytes. 1732 16

PEA-15 (phosphoprotein enriched in astrocytes 15 kDa) is a death effector domain-containing protein, which is involved in the regulation of apoptotic cell death. Since PEA-15 is highly expressed in cells of glial origin, we studied the role of PEA-15 in human malignant brain tumors. Immunohistochemical analysis of PEA-15 expression shows strong immunoreactivity in astrocytomas and glioblastomas. Phosphorylation of PEA-15 at Ser(116) is found in vivo in perinecrotic areas in glioblastomas and in vitro after glucose deprivation of glioblastoma cells. Overexpression of PEA-15 induces a marked resistance against glucose deprivation-induced apoptosis, whereas small interfering RNA (siRNA)-mediated downregulation of endogenous PEA-15 results in the sensitization to glucose withdrawal-mediated cell death. This antiapoptotic activity of PEA-15 under low glucose conditions depends on its phosphorylation at Ser(116). Moreover, siRNA-mediated knockdown of PEA-15 abolishes the tumorigenicity of U87MG glioblastoma cells in vivo. PEA-15 regulates the level of phosphorylated extracellular-regulated kinase (ERK)1/2 in glioblastoma cells and the PEA-15-dependent protection from glucose deprivation-induced cell death requires ERK1/2 signaling. PEA-15 transcriptionally upregulates the Glucose Transporter 3, which is abrogated by the inhibition of ERK1/2 phosphorylation. Taken together, our findings suggest that Ser(116)-phosphorylated PEA-15 renders glioma cells resistant to glucose deprivation-mediated cell death as encountered in poor microenvironments, for example in perinecrotic areas of glioblastomas.
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PMID:The PEA-15/PED protein protects glioblastoma cells from glucose deprivation-induced apoptosis via the ERK/MAP kinase pathway. 1770 May 18

Glioblastoma multiformes (GBMs) express increased aquaporin (AQP) 1 compared to normal brain. AQPs may contribute to edema, cell motility, and shuttling of H(2)O and H(+) from intracellular to extracellular space. We sought to gain insight into AQP1 function in GBM. In cultured 9L gliosarcoma cells, AQP1 expression was induced by dexamethasone, platelet-derived growth factor, NaCl, hypoxia, D-glucose (but not L-glucose), and fructose. Induction of AQP1 expression correlated with the level of glycolysis, maximized by increasing medium D-glucose or fructose and decreasing O(2), and was quantified by measuring lactate dehydrogenase (LDH) activity and medium lactate concentration. Upregulation of the protease cathepsin B was also observed in 9L cells cultured under glycolytic conditions. Immunohistochemical staining of human GBM specimens revealed increased coincident expression of AQP1, LDH, and cathepsin B in glioma cells associated with blood vessels at the tumor periphery. GBMs are known to exhibit aerobic glycolysis. Increased glucose metabolism at the tumor periphery may provide a scenario by which upregulation of AQP1, LDH, and cathepsin B contributes to acidification of the extracellular milieu and to invasive potential of glioma cells in perivascular space. The specific upregulation and metabolic consequences of increased AQP1 in gliomas may provide a therapeutic target, both as a cell surface marker and as a functional intervention.
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PMID:Regulation and function of aquaporin-1 in glioma cells. 1789 73

Tumor cell proliferation requires rapid synthesis of macromolecules including lipids, proteins, and nucleotides. Many tumor cells exhibit rapid glucose consumption, with most of the glucose-derived carbon being secreted as lactate despite abundant oxygen availability (the Warburg effect). Here, we used 13C NMR spectroscopy to examine the metabolism of glioblastoma cells exhibiting aerobic glycolysis. In these cells, the tricarboxylic acid (TCA) cycle was active but was characterized by an efflux of substrates for use in biosynthetic pathways, particularly fatty acid synthesis. The success of this synthetic activity depends on activation of pathways to generate reductive power (NADPH) and to restore oxaloacetate for continued TCA cycle function (anaplerosis). Surprisingly, both these needs were met by a high rate of glutamine metabolism. First, conversion of glutamine to lactate (glutaminolysis) was rapid enough to produce sufficient NADPH to support fatty acid synthesis. Second, despite substantial mitochondrial pyruvate metabolism, pyruvate carboxylation was suppressed, and anaplerotic oxaloacetate was derived from glutamine. Glutamine catabolism was accompanied by secretion of alanine and ammonia, such that most of the amino groups from glutamine were lost from the cell rather than incorporated into other molecules. These data demonstrate that transformed cells exhibit a high rate of glutamine consumption that cannot be explained by the nitrogen demand imposed by nucleotide synthesis or maintenance of nonessential amino acid pools. Rather, glutamine metabolism provides a carbon source that facilitates the cell's ability to use glucose-derived carbon and TCA cycle intermediates as biosynthetic precursors.
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PMID:Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. 1803 1

PEA-15 (Phosphoprotein enriched in astrocytes 15 kD) is a death effector domain-containing protein, which is involved in the regulation of apoptotic cell death. Since PEA-15 is highly expressed in cells of glial origin, we studied the role of PEA-15 in human malignant brain tumors. Immunohistochemical analysis of PEA-15 expression shows strong immunoreactivity in astrocytomas and glioblastomas. Phosphorylation of PEA-15 at Ser116 is found in vivo in perinecrotic areas in glioblastomas and in vitro after glucose deprivation of glioblastoma cells. Overexpression of PEA-15 induces a marked resistance against glucose deprivation-induced apoptosis, whereas siRNA-mediated down-regulation of endogenous PEA-15 results in the sensitization to glucose withdrawal-mediated cell death. This anti-apoptotic activity of PEA-15 under low glucose conditions depends on its phosphorylation at Ser116 Moreover, siRNA-mediated knockdown of PEA-15 abolishes the tumorigenicity of U87MG glioblastoma cells in vivo. PEA-15 regulates the level of phosphorylated ERK1/2 in glioblastoma cells and the PEA-15-dependent protection from glucose deprivation-induced cell death requires ERK1/2 signaling. PEA-15 transcriptionally up-regulates the glucose transporter 3, which is abrogated by the inhibition of ERK1/2 phosphorylation. Taken together, our findings suggest that Ser116-phosphorylated PEA-15 renders glioma cells resistant to glucose deprivation-mediated cell death as encountered in poor microenvironments, e.g. in perinecrotic areas of glioblastomas.
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PMID:[The PEA-15 protein induces resistance against glucose deprivation-induced cell death via the ERK/MAP kinase pathway]. 1831 33

Nitric Oxide (NO) releasing agents can serve as potent cytotoxic agents. However at present there are no effective ways to target delivery of NO donors like S-nitroso-N-acetyl-penicillamine (SNAP). SNAP conjugated to glucose (2-gluSNAP) can be readily transported across the membrane by GLUT 1 transporters. Therefore, sensitivity of cells to 2-gluSNAP may depend on glucose-transporter GLUT 1. We evaluated the cytotoxicity of SNAP and 2-gluSNAP on a GLUT 1 rich glioblastoma cell line T98G and GLUT 1 deficient osteoblastoma cell line 143B and its mitochondria-deficient variant rhoo (cell line 206). The cytotoxity of SNAP and 2-gluSNAP was assessed by clonogenic assay performed in the above cell lines in vitro. Immunoblotting and semi-quantitative real-time PCR assays were used to evaluate the expression of GLUT 1 transporter at protein and mRNA levels. The glioblastoma cell line T98G was more sensitive to 2-gluSNAP than unconjugated SNAP. SNAP and 2-gluSNAP affected the osteosarcoma cell lines 143B and rhoo poorly. Immunoblot analysis detected GLUT 1 protein in T98G cells and not in 143B or rhoo. There was about a 10-fold difference in GLUT 1 mRNA level in T98G cells compared to 143B and rhoo cell lines. This is consistent with our cytotoxicity studies and immunoblot analysis. Our results give credence to our hypothesis that the sensitivity to NO donors can be increased by glyco-conjugation and the cytotoxicity of the glyco-conjugated NO donors depends on the expression of GLUT 1 mRNA and protein.
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PMID:Differential expression of Glut 1 mRNA and protein levels correlates with increased sensitivity to the glyco-conjugated nitric oxide donor (2-glu-SNAP) in different tumor cell types. 1834 52

True multicentric glioblastoma multiforme (GBM) is rare and consists of separate distinct tumors in different cerebral lobes or hemispheres without any apparent route of dissemination. Few data are available describing its imaging using positron emission tomography (PET) with [18F]-fluoro-2-deoxy-D: -glucose (FDG). In this paper, we report on the case of a man with bifocal tumor in the right frontal and temporal lobes who underwent FDG-PET imaging. Visual and semiquantitative analysis showed two different metabolic patterns with much more intense uptake in the smaller temporal lesion. Subtotal surgical removal of the main frontal lesion allowed satisfactory control in the operative site, whereas the temporal lesion was rapidly progressive with occurrence of necrosis, which led to a second neurosurgery. The diagnosis of glioblastoma was confirmed by neuropathological examination in both cases but with much higher immunohistochemical expression of O(6)-methylguanine-DNA-methyltransferase (MGMT) in the temporal lesion. This report illustrates the potential interest of FDG-PET in multicentric GBMs to identify different metabolic patterns, in accordance with clinical, morphological, and molecular aggressiveness.
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PMID:FDG-PET to predict different patterns of progression in multicentric glioblastoma: a case report. 1856 92

The understanding of the mechanisms of cell-death execution and the role that they play in different diseases opens new therapeutic strategies. Currently, increasing evidence indicates that autophagy is a frequent cell-death mechanism, so the question arises: Could autophagy stimulation be considered an antitumor therapy? Several autophagy inducers have been used as anticancer agents and, although complete tumor eradication has not been demonstrated, the antitumor effect is very promising. We have recently demonstrated that strong autophagy stimulation mediated by the combined generation of cyanide and oxidative stress could efficiently suppress tumor growth in an aggressive brain cancer model such as glioblastoma. We have used the plant enzyme linamarase, which metabolizes the innocuous substrate linamarin to generate cyanide in a continuous and controlled way inducing mitochondrial fragmentation. Glucose oxidase addition induces oxidative stress that increases cell vacuolization. The combination of both insults favors mitochondrial engulfment by vacuoles accelerating cell death that is mediated by autophagy.
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PMID:Autophagy induction as an efficient strategy to eradicate tumors. 1871 58

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a critical role in angiogenesis, survival, metastasis, drug resistance, and glucose metabolism. Elevated expression of the alpha-subunit of HIF-1 (HIF-1alpha), which occurs in response to hypoxia or activation of growth factor pathways, is associated with poor prognosis in many types of cancer. Therefore, down-regulation of HIF-1alpha protein by RNA antagonists may control cancer growth. EZN-2968 is a RNA antagonist composed of third-generation oligonucleotide, locked nucleic acid, technology that specifically binds and inhibits the expression of HIF-1alpha mRNA. In vitro, in human prostate (15PC3, PC3, and DU145) and glioblastoma (U373) cells, EZN-2968 induced a potent, selective, and durable antagonism of HIF-1 mRNA and protein expression (IC(50), 1-5 nmol/L) under normoxic and hypoxic conditions associated with inhibition of tumor cell growth. Additionally, down-regulation of HIF-1alpha protein by EZN-2968 led to reduction of its transcriptional targets and of human umbilical vein endothelial cell tube formation. In vivo, administration of EZN-2968 to normal mice led to specific, dose-dependent, and highly potent down-regulation of endogenous HIF-1alpha and vascular endothelial growth factor in the liver. The effect can last for days after administration of single dose of EZN-2968 and is associated with long residence time of locked nucleic acid in certain tissues. In efficacy studies, tumor reduction was found in nude mice implanted with DU145 cells treated with EZN-2968. Ongoing phase I studies of EZN-2968 in patients with advanced malignancies will determine optimal dose and schedule for the phase II program.
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PMID:A RNA antagonist of hypoxia-inducible factor-1alpha, EZN-2968, inhibits tumor cell growth. 1897 94

Microdialysis enables measurement of the chemistry of the cerebral extracellular fluid. This study's objective was to utilise microdialysis to monitor levels of glucose, lactate, pyruvate, glutamate and glycerol in patients following surgery for intrinsic brain tumours, and to assess the concentration of growth factors, cytokines and other proteins involved in the pathogenesis of high-grade gliomas in vivo. Eight patients with suspected high-grade gliomas were studied. Seven of these underwent resection with one microdialysis catheter placed at the tumour resection margin and, in six of these seven cases, a second microdialysis catheter in macroscopically normal peritumour tissue. The remaining glioma patient had an image-guided biopsy with a single catheter inserted stereotactically at the tumour margin. Histology demonstrated WHO IV glioblastoma in five cases, WHO III anaplastic astrocytoma in two cases, and one cerebral lymphoma. In the high-grade gliomas (WHO IV and III), tumour margin microdialysates consistently showed significantly lower glucose, higher lactate/pyruvate (L/P) ratio, higher glutamate and higher glycerol, relative to peritumour microdialysates (P < 0.05). These results indicate that malignant glioma margin tissue is metabolically extremely active. There was great variability in the microdialysate concentrations of growth factors (TGFalpha, EGF, VEGF), cytokines (IL-1alpha, IL-1beta, IL-1ra, IL-6, IL-8), matrix metalloproteinases (MMP-2, MMP-9) and their endogenous inhibitors (TIMP-1, TIMP-2). Notably, microdialysates from the glioma resection margin demonstrated significantly higher IL-8 concentration and higher MMP-2/TIMP-1 ratio when compared to peritumour microdialysates (P < 0.05), suggesting an environment favouring invasion and angiogenesis at the tumour margin. Microdialysis is a promising technique to study in vivo glioma metabolism, and may assist in the development of new therapies.
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PMID:In vivo assessment of high-grade glioma biochemistry using microdialysis: a study of energy-related molecules, growth factors and cytokines. 1971 45


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