UMLS:C0017636 - FACTA Search

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Query: UMLS:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. In primary cultured human glioblastoma cells extracellular application of ATP triggered elevation in cytoplasmic calcium concentration ([Ca2+]i) mediated entirely by generation of inositol 1,4,5-trisphosphate (InsP3)-dependent Ca2+ release from endoplasmic reticulum Ca2+ stores followed by the activation of store-operated Ca2+ entry into the cells. 2. Sensitivity of P2Y purinoceptors to extracellular ATP was regulated by extracellular Ca2+: in Ca2+-free extracellular solution the threshold concentration of ATP that induced an increase in [Ca2+]i was reduced by one order of magnitude. 3. Activation of Ca2+ release and store-operated Ca2+ entry was dissociated: low concentrations of ATP induced substantial Ca2+ release without activation of Ca2+ entry; activation of the latter required higher ATP concentrations. 4. Mitochondria participated in buffering Ca2+ loads that resulted from store-operated Ca2+ influx; in contrast Ca2+ released from intracellular stores was not accumulated by the mitochondrial depot. 5. We conclude that ATP-induced Ca2+ responses are governed by several pathways with different sensitivities to the agonist. This enables cells to respond either with pure Ca2+ release from intracellular stores (at low ATP concentrations) or (at high ATP concentrations) the response is amplified by plasmalemmal Ca2+ influx. Store-operated Ca2+ entry increases mitochondrial Ca2+ content providing a link between cellular activation and mitochondrial function.
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PMID:Relations between intracellular Ca2+ stores and store-operated Ca2+ entry in primary cultured human glioblastoma cells. 980 92

Expression of angiogenic factors such as vascular endothelial growth factor (VEGF) under conditions of cell stress involves both transcriptional and translational events, as well as an important role for inducible endoplasmic reticulum (ER) chaperones. Coexpression of VEGF and 150-kDa oxygen-regulated protein (ORP), a novel ER chaperone, in human glioblastoma suggested a link between angiogenesis and ORP150. C6 glioma cells stably transfected with ORP150 antisense displayed selectively reduced ORP150 expression. Tumors raised after inoculation of immunocompromised mice with ORP150 antisense C6 glioma transfectants demonstrated an initial phase of growth comparable to wild-type C6 glioma cells which was followed by marked regression within 8 days. Decreased density of platelet/endothelial cell adhesion molecule 1-positive structures within the tumor bed was consistent with reduced angiogenesis in C6 gliomas expressing ORP150 antisense, compared with tumors derived from C6 cells overexpressing ORP150 sense or vector controls. In vitro, inhibition of ORP150 expression decreased release of VEGF into culture supernatants; in ORP150 antisense transfectants, VEGF accumulated intracellularly within the ER. These findings demonstrate a critical role for the inducible ER chaperone ORP150 in tumor-mediated angiogenesis via processing of VEGF, and, thus, highlight a new facet of angiogenic mechanisms amenable to therapeutic manipulation in tumors.
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PMID:Regulation of tumor angiogenesis by oxygen-regulated protein 150, an inducible endoplasmic reticulum chaperone. 1135 46

Hypericin, a natural polycyclic quinone extracted from Hypericum perforatum, has been recently shown to be a powerful sensitiser for photodynamic therapy (PDT). However, its intracellular localisation remains unclear and contradictory. In the present work we compared the intracellular localisation of hypericin in three cultured cell lines (adenocarcinoma cells WiDr, carcinoma cells NHIK 3025 and glioblastoma cells D54Mg) with the distribution of fluorescent probes specific to lysosomes (LysoTracker Blue DND-22), mitochondria (MitoTracker Green FM) and endoplasmic reticulum (ERTracker Blue-White DPX). It was shown that the hypericin staining pattern was different compared to the intracellular distribution of mitochondria or lysosomes. Hypericin was concentrated in the perinucleolar cytoplasmic area mainly on one side of the nucleus--the region rich in endoplasmic reticulum and Golgi. Sometimes nuclear envelope was also stained. Plasma membrane was not stained but the dye was often accumulated in the intercellular space between the tightly contacting WiDr cells in colonies. Hypericin concentrations of 10 microM or less were not toxic for WiDr cells in the dark. Orange light (lambda max approximately 600 nm; 6 mW/cm2) killed the cells stained with 1 microM hypericin with LD50 approximately 1 J/cm2.
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PMID:Intracellular localisation of hypericin in human glioblastoma and carcinoma cell lines. 1170 33

Modulation of host immune responses has emerged as a common strategy employed by herpesviruses both to establish life-long infections and to affect recovery from infection. Herpes simplex virus 1 (HSV-1) blocks the major histocompatibility complex (MHC) class I antigen presentation pathway by inhibiting peptide transport into the endoplasmic reticulum. The interaction of viral gene products with the MHC class II pathway, however, has not been thoroughly investigated, although CD4(+) T cells play an important role in human recovery from infection. We have investigated the stability, distribution, and state of MHC class II proteins in glioblastoma cells infected with wild-type HSV-1 or mutants lacking specific genes. We report the following findings. (i) Wild-type virus infection caused a decrease in the accumulation of class II protein on the surface of cells and a decrease in the endocytosis of lucifer yellow or dextran conjugated to fluorescein isothiocyanate but no decrease in the total amount of MHC class II proteins relative to the levels seen in mock-infected cells. (ii) Although the total amount of MHC class II protein remained unchanged, the amounts of cell surface MHC class II proteins were higher in cells infected with the U(L)41-negative mutant, which lacks the virion host shutoff protein, and especially high in cells infected with the gamma(1)34.5-negative mutant. We conclude that infected cells attempt to respond to infection by increased acquisition of antigens and transport of MHC class II proteins to the cell surface and that these responses are blocked in part by the virion host shutoff protein encoded by the U(L)41 gene and in large measure by the direct or indirect action of the infected cell protein 34.5, the product of the gamma(1)34.5 gene.
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PMID:Cell surface major histocompatibility complex class II proteins are regulated by the products of the gamma(1)34.5 and U(L)41 genes of herpes simplex virus 1. 1207 98

EGFRvIII is a mutant epidermal growth factor that promotes aggressive growth of glioblastomas. We made a plasmid that directed the expression of an EGFRvIII with three copies of the Flag epitope at its amino terminus. Flag-tagged EGFRvIII was expressed at the same levels as unmodified EGFRvIII, and showed the same subcellular localization. However, the Flag epitope could only be detected on EGFRvIII present in the endoplasmic reticulum; the epitope was covalently modified during trafficking of the receptor through the Golgi so that it was no longer recognized by anti-Flag antibody. This property was exploited to selectively purify nascent EGFRvIII from glioblastoma cells. Nascent EGFRvIII was found to copurify with a set of other proteins, identified by mass spectrometry as the two endoplasmic reticulum chaperones Grp94 and BiP, and the two cytosolic chaperones Hsc70 and Hsp90. The Hsp90-associated chaperone Cdc37 also co-purified with EGFRvIII, suggesting that Hsp90 binds EGFRvIII as a complex with this protein. Geldanamycin and radicicol, two chemically unrelated inhibitors of Hsp90, decreased the expression of EGFRvIII in glioblastoma cells. These studies show that nascent EGFRvIII in the endoplasmic reticulum associates with Hsp90 and Cdc37, and that the Hsp90 association is necessary to maintain expression of EGFRvIII.
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PMID:Interaction of Hsp90 with the nascent form of the mutant epidermal growth factor receptor EGFRvIII. 1247 Oct 35

Our laboratory demonstrated that endoplasmic reticulum iPLA2 (ER-iPLA2) activity protects renal cells from oxidant-induced cell death and lipid peroxidation. The goals of this study were to determine the PLA2 isoform(s) responsible for ER-iPLA2 activity in different species and tissues. ER-iPLA2 activity was observed in microsomes from rabbit and rat kidney, heart, and brain as well as in human kidney (Caki-1 and HEK293) and glioblastoma (A172) cell lines. Reverse transcriptase-polymerase chain reaction results demonstrated the presence of iPLA2gamma (group VIB PLA2) message in all tissues tested. Immunoblot analysis and PLA2 inhibitor studies with methyl arachidonyl fluorophosphonate and enantiomers of bromoenol lactone demonstrated that the ER-iPLA2 in rabbit kidney and heart and rat kidney is iPLA2gamma. These results demonstrate the expression of ER-iPLA2gamma (group VIB) across species and tissues, and suggest that iPLA2gamma may play critical roles in oxidant-induced cell injury.
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PMID:Identification and distribution of endoplasmic reticulum iPLA2. 1562 60

In an article presented in this issue of Molecular Pharmacology, Yacoub et al. (p. 589) examine the actions of 2-amino-N{4-5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-acetamide (OSU-03012) on both primary and glioblastoma cell lines. The authors found that OSU-03012 could induce tumor cell death by itself but also acted as a strong sensitizing agent to radiotherapy-induced cell death. Glioblastoma cells were also more sensitive to this compound than nontransformed astrocytes. Radiation-induced cell death was refractory to small interfering RNA-directed inhibition of PDK1 but not OSU-03012. These results indicate that OSU-03012, which has been thought to primarily mediate antitumor effects via the inhibition of PDK1, has actions independent of PDK1. Furthermore, the authors demonstrated that the effects of OSU-03012 were independent of ERB-B1-vIII and PTEN expression. These are important findings because they start to identify a new mechanism to sensitize glioblastoma cells and also suggest that OSU-03012 could be combined with existing inhibitors to further sensitize tumor cells. In glioblastoma cells, OSU-03012 seemed to induce apoptosis via endoplasmic reticulum stress-induced PERK-dependent signaling. OSU-03012-induced death of the glioblastoma was only weakly suppressed by the pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp, suggesting that OSU-03012-induced cell death was largely caspase-independent. Overall, these are exciting results and suggest that new more effective treatment options may be obtainable for people suffering from these deadly tumors.
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PMID:OSU-03012 in the treatment of glioblastoma. 1667 57

Glial cell line-derived neurotrophic factor (GDNF), a neurotrophic and differentiation factor, is expressed under several pathophysiological conditions but its regulatory signals have not yet been clarified. Here, we found that endoplasmic reticulum (ER) Ca(2+) discharge by thapsigargin induced GDNF mRNA as well as COX2 and GRP78 expression in rat C6 glioblastoma cells. GDNF mRNA was immediately induced and peaked at 2h by thapsigargin, and the alternative transcript consisting of exon 3 and exon 4 appeared to be most inducible. In spite of intracellular Ca(2+) perturbation, Ca(2+)-dependent PKC was not responsible for this induction. Instead, a PKCdelta-specific inhibitor, rottlerin, suppressed the thapsigargin-induced GDNF mRNA expression. On the other hand, thapsigargin transiently enhanced phosphorylation status of mitogen-activated protein kinase (MAPK) pathway, including extracellular signal-regulated kinase (Erk), p38 MAPK and c-JUN amino-terminal kinase1 (JNK1) simultaneously; whereas specific inhibitors against MEK1 and JNK only reduced the thapsigargin-induced GDNF mRNA expression. In addition, a pan-PKC inhibitor (Ro-31-8220) attenuated the thapsigargin-enhanced phosphorylation levels of Erk1/2 and JNK1, whereas rottlerin did not. Thus, the present study demonstrated that the thapsigargin-stimulated ER Ca(2+) discharge up-regulated GDNF gene expression through both MAPK-dependent and -independent pathways in C6 glioblastoma cells.
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PMID:ER calcium discharge stimulates GDNF gene expression through MAPK-dependent and -independent pathways in rat C6 glioblastoma cells. 1683 15

Radiotherapy is the primary and most important adjuvant therapy for malignant gliomas. Although the mechanism of radiation resistance in gliomas has been studied for decades, it is still not clear how the resistance is related with functions of molecular chaperones in the endoplasmic reticulum. Calreticulin (CRT) is a Ca(2+)-binding molecular chaperone in the endoplasmic reticulum. Recently, it was reported that changes in intracellular Ca(2+) homeostasis play a role in the modulation of apoptosis. In the present study, we found that the level of CRT was higher in neuroglioma H4 cells than in glioblastoma cells (U251MG and T98G), and was well correlated with the sensitivity to gamma-irradiation. To examine the role of CRT in the radiosensitivity of malignant gliomas, the CRT gene was introduced into U251MG cells, which express low levels of CRT, and the effect of overexpression of CRT on the radiosensitivity was examined. The cells transfected with the CRT gene exhibited enhanced radiation-induced apoptosis compared with untransfected control cells. In CRT-overexpressing cells, cell survival signaling via Akt was markedly suppressed. Furthermore, the gene expression of protein phosphatase 2Ac alpha (PP2Ac alpha), which is responsible for the dephosphorylation and inactivation of Akt, was up-regulated in CRT-overexpressing cells, and the regulation was dependent on Ca(2+). Thus, overexpression of CRT modulates radiation-induced apoptosis by suppressing Akt signaling through the up-regulation of PP2Ac alpha expression via altered Ca(2+) homeostasis. These results show the novel mechanism by which CRT is involved in the regulation of radiosensitivity and radiation-induced apoptosis in malignant glioma cells.
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PMID:Calreticulin, a molecular chaperone in the endoplasmic reticulum, modulates radiosensitivity of human glioblastoma U251MG cells. 1695 Nov 81

While Newcastle disease virus (NDV) causes serious infections in birds, it is apparently nonpathogenic in mammalian species, including humans. Previous observations and small-scale clinical trials indicated that NDV exerts oncolytic effects. Isolates of NDV were found to have selective affinity to transformed cells. We previously showed that the attenuated NDV strain MTH-68/H causes apoptotic cell death in cultures of PC12 rat pheochromocytoma cells. The aim of the present study was to extend MTH-68/H cytotoxicity testing with human tumor cell lines and to analyze certain biochemical aspects of its oncolytic effect. MTH-68/H was found to be able to kill a wide range of transformed cells by apoptosis. While caspase-8 and caspase-9 are not involved in MTH-68/H-induced apoptosis, activation of caspase-3 and caspase-12 was detected in virus-infected PC12 cells. A human glioblastoma cell line with repressible expression of the p53 protein did not show any difference in MTH-68/H sensitivity in its p53-expressing and p53-depleted states, indicating that the apoptotic process induced by MTH-68/H does not depend on p53. Apoptosis was accompanied by virus replication in two tumor cell lines tested (PC12 cells and HeLa human cervical cells), and signs of endoplasmic reticulum stress (phosphorylation of protein kinase R-like endoplasmic reticulum kinase and eIF2alpha) were also detected in transformed cells. In contrast, proliferation of nontransformed mouse and rat fibroblast cell lines and human primary fibroblasts was not affected by MTH-68/H treatment. MTH-68/H thus selectively kills tumor cell cultures by inducing endoplasmic reticulum stress leading to p53-independent apoptotic cell death.
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PMID:p53-independent endoplasmic reticulum stress-mediated cytotoxicity of a Newcastle disease virus strain in tumor cell lines. 1721 92

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