UMLS:C0017638 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

C6 glioma - Ca2+ depletion - proliferation arrest morphology change - CDK inhibitor In this study, we investigated the role of the intracellular calcium store in modulating the cellular proliferation and the expression of cell cycle regulatory proteins in cultured C6 glioma cells. By means of microspectrofluorimetry and Ca(2+)-sensitive indicator fura-2, we found that the intracellular Ca2+ pump inhibitors, thapsigargin (TG) irreversibly and 2,5-ditert-butyl-hydroquinone (DBHQ) reversibly depleted the Ca(2+)-store accompanied with the induction of G0/G1 arrest, an increase in glial fibrillary acidic protein (GFAP) expression and morphological changes from a round flat shape to a differentiated spindle-shaped cell. The machinery underlying these changes induced by Ca(2+)-store depletion was investigated. The results indicated that Ca(2+)-store depletion caused an increased expression of p21 and p27 proteins (cyclin-dependent kinase inhibitors), with unchanged mutant p53 protein of C6 cells but reduced amounts of the cell cycle regulators: cyclin-dependent kinase 2 (CDK2), cdc2, cyclin C, cyclin D1, cyclin D3 and proliferating cell nuclear antigen (PCNA) in a time-dependent manner. These findings indicate a new function of the endoplasmic reticulum (ER) Ca2+ store in regulating cellular proliferation rate through altering the expression of p21 and p27 proteins. Moreover, cellular differentiation as revealed by spindle-shaped morphology and induced GFAP expression were also modulated by the ER Ca2+ store. The implication of this finding is that the abnormal growth of cancer cells such as C6 glioma cells may be derived from a signalling of the ER which can be manipulated by depleting the Ca2+ store.
...
PMID:Proliferation arrest and induction of CDK inhibitors p21 and p27 by depleting the calcium store in cultured C6 glioma cells. 1060 59

The effects of 2,5-di(tert-butyl)-1,4-benzohydroquinone (tBHQ), a synthetic phenolic antioxidant and a blocker of the sarco-endoplasmic ATPase, were evaluated on low and high voltage-activated Ca(2+) currents (ICas) with rodent dorsal root ganglion, hippocampal, and motor neurons. In all cell types tested, tBHQ (IC(50) = 35 microM) blocked ICa at concentrations used to inhibit sarco-endoplasmic ATPase. This effect was specific to tBHQ because the other sarco-endoplasmic reticulum calcium ATPase pump inhibitors (thapsigargin and cyclopiazonic acid) had no effect. Selective blockade of the N-type current with omega-conotoxin GVIA and of P- (motoneuron) or Q-type currents (hippocampal neuron) with omega-agatoxin IVA indicated that tBHQ inhibited N, P, and Q types of ICa. tBHQ had no effect on nitrendipine-sensitive (L-type) and residual drug-resistant (R-type) ICa, nor on the low voltage-activated T-type ICa. Contrary to neuronal cells, the L-type ICa was inhibited by tBHQ in a differentiated mouse neuroblastoma and rat glioma hybrid cell line. Injection of cDNAs encoding the alpha1A, alpha1B, alpha1C, and alpha1E subunits into oocytes showed that tBHQ blocked ICas at the level of the pore-forming protein. This effect of tBHQ on ICa should be considered when interpreting results obtained with tBHQ used on neuronal preparations. It also may be useful for developing new strategies for the generation of more potent intracellular calcium transient inhibitors.
...
PMID:Sarco-endoplasmic ATPase blocker 2,5-Di(tert-butyl)-1, 4-benzohydroquinone inhibits N-, P-, and Q- but not T-, L-, or R-type calcium currents in central and peripheral neurons. 1086 Sep 23

The anticonvulsant sodium valproate has been shown to be an effective treatment for bipolar disorder, however, its precise mechanism of action has yet to be determined. It has been suggested that adaptational changes in gene expression are critical for valproate's prophylactic effects. Previous studies in our lab have shown that one gene that may be regulated by valproate is the 78-kilodalton glucose-regulated protein (GRP78). We report that treatment of rat C6 glioma cells with valproate can also increase the expression of additional endoplasmic reticulum stress proteins, GRP94 and calreticulin. All three proteins showed similar concentration-dependent increases in messenger RNA abundance. Chronic (seven days) treatment significantly increased GRP78 and GRP94 messenger RNA expression, whereas calreticulin expression increased after both acute and chronic treatment. Increases in mRNA expression corresponded to a similar increase in protein expression. The roles of GRP78, GRP94 and calreticulin as molecular chaperones and calcium binding proteins, suggest that these results might have functional relevance to the therapeutic action of valproate.
...
PMID:Increased expression of endoplasmic reticulum stress proteins following chronic valproate treatment of rat C6 glioma cells. 1096 59

The effect of tamoxifen on Ca(2+) signaling and viability in Madin Darby canine kidney (MDCK) cells was investigated by using fura-2 as a Ca(2+) probe. Tamoxifen evoked a rise in cytosolic free Ca(2+) levels ([Ca(2+)](i)) concentration-dependently between 1 and 50 microM with an EC50 of 10 microM. The response was decreased by extracellular Ca(2+) removal. In Ca(2+)-free medium, pretreatment with 5 microM tamoxifen abolished the [Ca(2+)](i) increase induced by the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (1 microM), but pretreatment with brefeldin A (50 microM; a Ca(2+) mobilizer of the Golgi complex), thapsigargin (an inhibitor of the endoplasmic reticulum Ca(2+) pump), and carbonylcyanide m-chlorophenylhydrazone (CCCP; a mitochondrial uncoupler), only partly inhibited tamoxifen-induced [Ca(2+)](i) increases. This suggests that tamoxifen released Ca(2+) from multiple pools. Addition of 3 mM Ca(2+) induced a [Ca(2+)](i) rise after pretreatment with 5 microM tamoxifen in Ca(2+)-free medium. Inhibiting inositol 1,4,5-trisphosphate formation with the phospholipase C inhibitor U73122 (2 microM) did not alter 5 microM tamoxifen-induced Ca(2+) release. The [Ca(2+)](i) increase induced by 5 microM tamoxifen was not altered by La(3+), nifedipine, verapamil, or diltiazem. Tamoxifen (1-10 microM) decreased cell viability in a concentration- and time-dependent manner. Tamoxifen (5 microM) also increased [Ca(2+)](i) in neutrophils, bladder cancer cells, and prostate cancer cells from humans and glioma cells from rats. Collectively, it was found that tamoxifen increased [Ca(2+)](i) in MDCK cells by releasing Ca(2+) from multiple Ca(2+) stores in a manner independent of the production of inositol 1,4, 5-trisphosphate and also by triggering Ca(2+) influx from extracellular space. The [Ca(2+)](i) increase was accompanied by cytotoxicity.
...
PMID:Dual effect of tamoxifen, an anti-breast-cancer drug, on intracellular Ca(2+) and cytotoxicity in intact cells. 1100 Jan

The proteasome is a multiprotein complex that is involved in the intracellular protein degradation in eukaryotes. Here, we show that human malignant glioma cells are susceptible to apoptotic cell death induced by the proteasome inhibitors, MG132 and lactacystin. The execution of the apoptotic death program involves the processing of caspases 2, 3, 7, 8, and 9. Apoptosis is inhibited by ectopic expression of X-linked inhibitor of apoptosis (XIAP) and by coexposure to the broad-spectrum caspase inhibitor, benzoyl-VAD-fluoromethyl ketone (zVAD-fmk), but not by the preferential caspase 8 inhibitor, crm-A. It is interesting that specific morphological alterations induced by proteasome inhibition, such as dilated rough endoplasmic reticulum and the formation of cytoplasmic vacuoles and dense mitochondrial deposits, are unaffected by zVAD-fmk. Apoptosis is also inhibited by ectopic expression of Bcl-2 or by an inhibitor of protein synthesis, cycloheximide. Further, cytochrome c release and disruption of mitochondrial membrane potential are prominent features of apoptosis triggered by proteasome inhibition. Bcl-2 is a stronger inhibitor of cytochrome c release than zVAD-fmk. XIAP and crm-A fail to modulate cytochrome c release. These data place cytochrome c release downstream of Bcl-2 activity but upstream of XIAP- and crm-A-sensitive caspases. The partial inhibition of cytochrome c release by zVAD-fmk indicates a positive feedback loop that may involve cytochrome c release and zVAD-fmk-sensitive caspases. Finally, death ligand/receptor interactions, including the CD95/CD95 ligand system, do not mediate apoptosis induced by proteasome inhibition in human malignant glioma cells.
...
PMID:Proteasome inhibitor-induced apoptosis of glioma cells involves the processing of multiple caspases and cytochrome c release. 1108 Jan 80

Presynaptic varicosities of the model neuronal cell line NG108-15, a cholinergic neuroblastoma cell x glioma cell hybrid capable of innervating striated myotubes, were examined for the presence of inositol 1,4,5-trisphosphate (IP3)-sensitive and Ca2+-activated (ryanodine-sensitive) Ca2+ stores using confocal microscopic imaging of Ca2+-sensitive fluorescent dye loaded into the cells. Initial demonstration of the presence of IP3 receptors and ryanodine receptors in the NG108-15 varicosities was obtained using immunocytochemistry. Treatment of NG108-15 cells with bradykinin (0.1 microM), whose receptor is linked to IP3 generation, and separately, caffeine (10 mM), an activator of endoplasmic reticulum ryanodine receptors, resulted in substantial increases in [Ca2+]i in the varicosities. K+-evoked changes in [Ca2+]i in the varicosities were reduced (52 %) after emptying the ryanodine-sensitive Ca2+ store using caffeine (10 mM), but were not affected by prior depletion of the IP3-sensitive Ca2+ store using thapsigargin (1 microM). Bradykinin-induced changes in [Ca2+]i were abolished following depletion of the IP3-sensitive Ca2+ store using thapsigargin (1 microM) and were reduced (72 %) by prior emptying of the ryanodine-sensitive Ca2+ store with caffeine (10 mM). The same results were obtained when the varicosities of the NG108-15 cells had formed synaptic junctions with co-cultured rat hindlimb myotubes. Taken together, the results suggest that, in the varicosities, activation of the IP3 pathway evoked the release of Ca2+ from the IP3-sensitive store, which, in turn, secondarily induced the release of Ca2+ from the ryanodine-sensitive store via Ca2+-induced Ca2+ release, and that depolarization-induced Ca2+ entry evoked Ca2+-induced Ca2+ release only from the ryanodine-sensitive store. Thus, functional internal Ca2+ stores are inherent components of presynaptic varicosities in this neural cell line.
...
PMID:Functional IP3- and ryanodine-sensitive calcium stores in presynaptic varicosities of NG108-15 (rodent neuroblastoma x glioma hybrid) cells. 1110 42

The effect of fluoxetine on Ca2+ signaling in Madin-Darby canine kidney (MDCK) cells was investigated by using fura-2 as a Ca2+ probe. Fluoxetine increased [Ca2+]i concentration-dependently between 5 microM and 200 microM with an EC50 value of 40 microM. The response was reduced by external Ca2+ removal by 30%40%. In Ca2+-free medium pretreatment with 1 microM thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+ pump, abolished 100 microM fluoxetine-induced Ca2+ release. Addition of 3 mM Ca2+ to Ca2+-free medium increased [Ca2+]i when cells were pretreated with 100 microM fluoxetine. Suppression of 1,4,5-trisphosphate (IP3) formation by 2 microM U73122 (a phospholipase C inhibitor) did not affect 100 microM fluoxetine-induced Ca2+ release. Fluoxetine (5-100 microM) also increased [Ca2+]i in neutrophils, prostate cancer cells and bladder cancer cells from human and rat glioma cells.
...
PMID:Fluoxetine-induced Ca2+ signals in Madin-Darby canine kidney cells. 1119 31

Mammalian cells are capable of committing "active suicide" or apoptosis in response to specialized pathological mechanisms employing a phylogenetically developed intrinsic program of death, triggered by signal transduction through specific receptors. Changes in cellular structure such as: 1) condensation of the nuclear (chromatin) and cytoplasmic structures (especially the mitochondria); 2) blebbing of the cell membrane; 3) characteristic swelling of the endoplasmic reticulum; and 4) fragmentation of the cells in membrane bound apoptotic bodies, are the dramatic signs of total cell destruction. Apoptosis requires energy in the from of ATP, indicating that programmed cell death (PCD), as opposed to necrosis, is an energy dependent, active physiological and pathophysiological phenomenon. During this immunocytochemical study, we observed the presence of PCD in the prenatal thymus and various human neoplastically transformed tissues. During the intrauterine ontogenesis, in thymocytes or resting T lymphocytes, p53 tumor suppressor protein was identified to be a critical mediator of PCD in response to DNA damage. The cellular interaction of immature, cortical thymocytes (characterized by a double positive CD4+CD8+TCRlow immunophenotype-IP) with thymic RE cells induces positive selection of T lymphocytes that recognize, but are not activated, by self-MHC molecules (tolerance induction). Double positive CD4+CD8+CD3- thymocytes undergo FasL-mediated apoptosis, while CD4+CD8+CD3+ cells use the CD3 mediated pathway of PCD. Two step, apoptotic cell death is mainly restricted to the CD4+CD8+TCR dull thymocyte subpopulation. T-lymphocytes which do not undergo positive selection are killed by apoptosis in response to a number of intrinsic and extrinsic factors, such as chemical toxins, viral infections, X- and UV irradiation, mild hyperthermia, the actions of various hormones, extracellular survival factors, calcium ionophores (such as A23187), various chemotherapeutic drugs (adriamycin, actinomycin D, etc) and antibodies directed to the CD3-TCR (T cell receptor) complex. Immature thymocytes also undergo a second selective process, so-called negative selection, when thymic stromal cells eliminate autoreactive T lymphocytes. As a typical model of embryonal neoplasms, we observed 34 childhood PNET/MED tissues samples. A systematic observation for the presence of apoptosis related markers (especially FasR) and cells in PCD was carried out. A strong expression (intensity of staining: "A"--the highest possible; number of stained neoplastic cells: +++ to ++++, between 50% to 90%) of FasR was detected. We also observed 42 childhood glial tumors, divided as follows: 6 pilocytic ASTRs; 14 low grade ASTRs; 16 anaplastic ASTRs; and 6 GBMs. The GBMs represent an end-stage brain tumor IP dedifferentiation of glial origin. During the immunocytochemical screening of these 42 childhood ASTRs, we detected strong expression (intensity of staining: "A"--the highest possible; number of stained cells: ++ to ++++, between 20% to 90%) of FasR, employing 4 microns thick, formalin fixed, paraffin-wax embedded tissue slides. FasR expression was rated high, 70% to 90% on the tumor cells in pylocytic ASTRs, lowered to 50% to 60% on the neoplastic cells in low grade ASTRs, even lower between 30% to 40% in anaplastic ASTRs and significantly lower, between 20% to 35% on the neoplastically transformed cells of GBM tissues. The presence of apoptotic neoplastic cells was also regularly detected in other human adult neoplasms, such as thyroid, pancreatic, hepatocellular, gastric, colon, breast, ovarian, prostata, and renal cell carcinomas, as well as, in Hodgkin and non-Hodgkin lymphomas and some sarcomas. The expression of apoptosis related cell surface molecules on the surface of both neoplastically transformed cells and on tumor cell specific, cytotoxic T lymphocyte (CTL) surfaces (FasR-FasL system) raises a distinct possibility of active PCD induction in CTL by tumor cells. Juxtacrine interactions between CTL and neoplastically transformed cells, coupled with observations that tumor cells can modulate the intracellular, signaling domains of cell surface receptors to elicit responses quite often contrary to the expected, may even provide a way for CTL to enhance the proliferation and dedifferentiation of cancer cells. Adoptive cellular immunotherapies employing CTL raised against autologous neoplastically transformed cells in vitro should be employed in the control of minimal residual disease following surgical resection of the primary malignant growth.
...
PMID:The role of apoptosis in normal ontogenesis and solid human neoplasms. 1120 98

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.
...
PMID:Regulation of tumor angiogenesis by oxygen-regulated protein 150, an inducible endoplasmic reticulum chaperone. 1135 46

We examined the effects of dissolved nitric oxide (NO) gas on cytoplasmic calcium levels ([Ca(2+)](i)) in C6 glioma cells under anoxic conditions. The maximum elevation (27 +/- 3 nM) of [Ca(2+)](i) was reached at 10 microM NO. A second application of NO was ineffective if the first was >0.5 microM. The NO donor diethylamine/NO mimicked the effects of NO. Acute exposure of the cells to low calcium levels was without effect on the NO-evoked response. Thapsigargin (TG) increased [Ca(2+)](i) and was less effective if cells were pretreated with NO. Hemoglobin inhibited the effects of NO at a molar ratio of 10:1. 8-Bromo-cGMP was without effect on the NO-evoked response. If cells were pretreated with TG or exposed chronically to nominal amounts of calcium, NO decreased [Ca(2+)](i). The results suggest that C6 glioma cells have two receptors for NO. One receptor (NO(A)) elevates [Ca(2+)](i) and resides on the endoplasmic reticulum (ER). The other receptor (NO(B)) decreases [Ca(2+)](i) and resides on the plasmalemma or the ER. The latter receptor dominates when the level of calcium within intracellular stores is diminished.
...
PMID:Regulation of cytoplasmic calcium levels by two nitric oxide receptors. 1150 65

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>