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)

The mammalian target of rapamycin (mTOR) is a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and a central modulator of cell proliferation in malignant gliomas. Therefore, the targeting of mTOR signaling is considered a promising therapy for malignant gliomas. However, the mechanisms underlying the cytotoxic effects of a selective mTOR inhibitor, rapamycin, on malignant glioma cells are poorly understood. The purpose of this study was thus to elucidate how rapamycin exerts its cytotoxic effects on malignant glioma cells. We showed that rapamycin induced autophagy but not apoptosis in rapamycin-sensitive malignant glioma U87-MG and T98G cells by inhibiting the function of mTOR. In contrast, in rapamycin-resistant U373-MG cells, the inhibitory effect of rapamycin was minor, although the phosphorylation of p70S6 kinase, a molecule downstream of mTOR, was remarkably inhibited. Interestingly, a PI3K inhibitor, LY294002, and an Akt inhibitor, UCN-01 (7-hydroxystaurosporine), both synergistically sensitized U87-MG and T98G cells as well as U373-MG cells to rapamycin by stimulating the induction of autophagy. Enforced expression of active Akt in tumor cells suppressed the combined effects of LY294002 or UCN-01, whereas dominant-negative Akt expression was sufficient to increase the sensitivity of tumor cells to rapamycin. These results indicate that rapamycin exerts its antitumor effect on malignant glioma cells by inducing autophagy and suggest that in malignant glioma cells a disruption of the PI3K/Akt signaling pathway could greatly enhance the effectiveness of mTOR inhibitors.
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PMID:Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. 1583 67

The contribution of Fas (CD95/APO-1) to cell death mechanisms of differentiated neurons is controversially discussed. Rat cerebellar granule neurons (CGNs) express high levels of Fas in vitro but are resistant to FasL (CD95L/APO-1L/CD178)-induced apoptosis. We here show that this resistance was mediated by a phosphatidylinositol 3-kinase (PI 3-kinase)-Akt/protein kinase B (PKB)-dependent expression of lifeguard (LFG)/neuronal membrane protein 35. Reduction of endogenous LFG expression by antisense oligonucleotides or small interfering RNA lead to increased sensitivity of CGNs to FasL-induced cell death and caspase-8 cleavage. The inhibition of PI 3-kinase activity sensitized CGNs to FasL-induced caspase-8 and caspase-3 processing and caspase-dependent fodrin cleavage. Pharmacological inhibition of PI 3-kinase, overexpression of the inhibitory protein IkappaB, or cotransfection of an LFG reporter plasmid with dominant-negative Akt/PKB inhibited LFG reporter activity, whereas overexpression of constitutively active Akt/PKB increased LFG reporter activity. Overexpression of LFG in CGNs interfered with the sensitization to FasL by PI 3-kinase inhibitors. In contrast to CGNs, 12 glioma cell lines, which are sensitive to FasL, did not express LFG. Gene transfer of LFG into these FasL-susceptible glioma cells protected against FasL-induced apoptosis. These results demonstrate that LFG mediated the FasL resistance of CGNs and that, under certain circumstances, e.g., inhibition of the PI 3-kinase-Akt/PKB pathway, CGNs were sensitized to FasL.
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PMID:FasL (CD95L/APO-1L) resistance of neurons mediated by phosphatidylinositol 3-kinase-Akt/protein kinase B-dependent expression of lifeguard/neuronal membrane protein 35. 1603 86

Previously we have shown that platelet-derived growth factor (PDGF) rapidly increases the activity of the neuronal glutamate transporter, EAAC1. This increase in activity is associated with a rapid (within minutes) redistribution of transporter from a subcellular compartment to the plasma membrane and is blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K). Similar effects of PI3K inhibitors have been observed for insulin-dependent up-regulation of the GLUT4 subtype of glucose transporter. Although GLUT4 regulation also depends on the serine-threonine kinase (Akt/protein kinase B), a downstream target of PI3K, the downstream effectors responsible of PDGF-dependent regulation of EAAC1 have not been identified. In the present study, PDGF increased the level of Akt phosphorylation (Ser 473) in C6 glioma cells, a cell line that has been used to study regulated trafficking of endogenous EAAC1. Two inhibitors of PI3K blocked this effect. In transient transfection studies, a dominant negative mutant of Akt-1 blocked PDGF-induced redistribution of epitope-tagged EAAC1 (myc-EAAC1). Conversely, constitutively active Akt-1 (CA Akt-1) increased the cell surface expression of myc-EAAC1. A lentiviral vector engineered to express CA Akt-1 increased Akt activation, cell surface expression of endogenous EAAC1, and Na(+)-dependent glutamate transport activity. Together, these studies suggest that Akt is required for PDGF-induced regulation of EAAC1.
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PMID:Evidence that Akt mediates platelet-derived growth factor-dependent increases in activity and surface expression of the neuronal glutamate transporter, EAAC1. 1618 22

The phosphatidylinositol 3-kinase pathway is an important regulator of a wide spectrum of tumor-related biological processes, including cell proliferation, survival, and motility, as well as neovascularization. Protein kinase B/Akt is activated in a complex manner through the phosphorylation of protein kinase B/Akt on Thr308 and Ser473. Although protein-dependent kinase-1 has been shown to phosphorylate Akt at Thr308, it is not clear whether there is a distinct kinase that exclusively phosphorylates Akt at Ser473. A possible candidate is integrin-linked kinase (ILK), which has been shown to phosphorylate Akt at Ser473 in vitro. ILK is a multidomain focal adhesion protein that is believed to be involved in signal transmission from integrin and growth factor receptors. Further, ILK is implicated in the regulation of anchorage-dependent cell growth/survival, cell cycle progression, invasion and migration, and tumor angiogenesis. In this study, we tested the hypothesis that ILK inhibition would inhibit these processes in gliomas in which it is constitutively expressed. We found that a newly developed small-molecule compound (QLT0267) effectively inhibited signaling through the ILK/Akt cascade in glioma cells by blocking the phosphorylation of Akt and downstream targets, including mammalian target of rapamycin and glycogen synthase kinase-3beta. Treatment of glioma cells with 12.5 micromol/L QLT0267 inhibited cell growth by 50% at 48 hours. An anchorage-dependent cell growth assay confirmed the cell growth-inhibitory effect of QLT0267. Further, the decrease in cell growth was associated with a dramatic accumulation of cells in the G2-M phase of the cell cycle. Although the cell growth-inhibitory effects of the ILK inhibitor were achieved only at a high concentration, the QLT0267 was able to reduce cellular invasion and angiogenesis at much lower concentrations as shown by in vitro invasion assays and vascular endothelial growth factor secretion. Thus, blocking the ILK/Akt pathway is a potential strategy for molecular targeted therapy for gliomas.
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PMID:Targeting integrin-linked kinase inhibits Akt signaling pathways and decreases tumor progression of human glioblastoma. 1627 89

Gliomas remain to be an unresolved medical problem. Better understanding of complex regulation and key molecules involved in glioma pathology are needed for designing new and effective treatment modalities. Activation of mitogen-activated protein kinase/extracellular signal regulated kinase (ERK) pathway is known to be having a critical role in cell proliferation and differentiation during the invasion and metastasis of the tumor cells. In the present study, N-ethyl N-nitrosourea induced glioma rat model was used to understand the role of ERK1/2 and Akt pathways in the progression of tumor malignancy. Twenty-four glioma rat brains of early (P90) and progressive (P180) stages were used for histological and immunoblot analysis. Results have shown increased levels of activated ERK1/2, activated Akt or protein kinase B, Bcl-2 and pBad in the glioma rats. This study may indicate increased cell proliferation and angiogenesis, mediated through activation of both ERK and Akt pathways along with increased levels of pBad. Further, pAkt and Bcl-2 levels in the progressive stage glioma rats may indicate existence of sustained tumor cell survival signals. Moreover, enhanced pBad levels in tumor may indicate that there are anti-apoptotic mechanisms, further making the malignant cells resistant to apoptosis.
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PMID:pERK, pAkt and pBad: a possible role in cell proliferation and sustained cellular survival during tumorigenesis and tumor progression in ENU induced transplacental glioma rat model. 1694 16

Treatment of rat glioma C6 cells with the beta-receptor agonist isoproterenol induces a massive increase in cAMP. Concomitantly the cells change their morphology from a fibroblast-type to an astrocyte-like (stellated) cell shape. The stellated morphology can be completely reverted by thrombin and sphingosine-1-phosphate (S-1-P) but also to a certain extent by clinical concentrations of volatile anesthetics. The anesthetic-induced reversion of the stellated cell shape seems to be mediated by a number of cellular alterations. Central to the effect is most likely a RhoA/Rho-kinase activation, but also the MAPKK/MEK and the Akt/protein kinase B pathway are activated by the anesthetics. With the use of specific inhibitors we were able to show that activation of the MAPKK/MEK pathway inhibits, whereas activation of the Akt/protein kinase B pathway stimulates the reversal of the stellated cell shape by the anesthetics. In summary, volatile anesthetics affect the morphology of rat glioma C6 cells by activation of the RhoA/Rho kinase, the MAPKK/MEK, and the Akt/protein kinase B signaling pathways.
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PMID:Volatile anesthetics affect the morphology of rat glioma C6 cells via RhoA, ERK, and Akt activation. 1749 63

Heparanase is an endoglycosidase that degrades heparan sulfate, the main polysaccharide constituent of the extracellular matrix (ECM) and basement membrane. Expression of the heparanase gene is associated with the invasion and metastatic potential of a variety of tumor-derived cell types. However, the roles of heparanase in the regulation of gene expression and the subsequent cell function changes other than invasion are not clear. In the current study, we overexpressed the human heparanase gene in a human U251n glioma cell line. We found that heparanase-overexpression significantly increased cell invasion, proliferation, anchorage-independent colony formation and chemotactic migration towards fetal bovine serum (FBS)-supplied medium and stromal cell-derived factor-1 (SDF-1). These phenotypic appearances were accompanied by enhanced protein kinase B (AKT) phosphorylation. Focal adhesion kinase (FAK) and extracellular signal-regulated kinase 1 (ERK1) signaling were not altered by heparanase-overexpression. These results indicate that heparanase has pleiotropic effects on tumor cells.
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PMID:Increased chemotactic migration and growth in heparanase-overexpressing human U251n glioma cells. 1864 7

S-Adenosylhomocysteine (SAH) is a risk factor for many diseases, including tumor progression and neurodegenerative disease. In this study, we examined the hypothesis that SAH may indirectly enhance the invasion of C6 glioma cells by induction of matrix metalloproteinase-2 (MMP-2) secreted from the murine microglia BV2 cells. We obtained conditioned medium (CM) by incubating BV2 cells with SAH (1-50nM) for 24 h. We found that the SAH-containing CM (SAH-BV2-CM) strongly enhanced the invasiveness of C6 glioma cells and that this effect increased with increasing concentrations of SAH in the SAH-BV2-CM. The effect of CM could be attributed to its MMP-2 activity, as a result of increased protein and messenger RNA expression of MMP-2 in BV2 cells induced by SAH. In BV2 cells treated with SAH, the binding abilities of nuclear factor-kappa B (NF-kappaB) and stimulatory protein-1 (Sp1) to the MMP-2 promoter were increased, whereas the level of NF-kappaB inhibitor was decreased. In addition, SAH significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3-kinase/serine/threonine protein kinase (or protein kinase B) (PI3K/Akt) proteins but did not affect that of c-Jun NH2-terminal kinase or p38. Pretreatment of BV2 cells with an inhibitor specific for ERK (U0126) markedly abated the expression of ERK and MMP-2. Furthermore, SAH significantly and dose dependently decreased tissue inhibitor of metalloproteinase-2 (TIMP-2) in BV2 cells. Thus, SAH may induce the invasiveness of C6 glioma cells by decreased TIMP-2 expression and increased MMP-2 expression in BV2 cells. The latter effect is likely mediated through the ERK and PI3K/Akt pathways, with increased binding activities of NF-kappaB and Sp1 to the MMP-2 gene promoter.
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PMID:S-Adenosylhomocysteine promotes the invasion of C6 glioma cells via increased secretion of matrix metalloproteinase-2 in murine microglial BV2 cells. 1977 Apr 85

Resveratrol (trans-3,4', 5-trihydroxystilbene) is a naturally occurring polyphenolic compound that has antiinflammatory, antioxidant, neuroprotective properties and acts as a chemopreventive agent. Resveratrol causes cell cycle arrest and induces apoptotic cell death in various types of cancer cells. In the current studies, the effect of resveratrol on phosphoinositide kinase-3 (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway was examined in human U251 glioma cells. Resveratrol decreased both the expression and phosphorylation of Akt. Inhibitors of PI3K (LY294002) and Akt (SH-6) enhanced resveratrol-induced LDH release and caspase-3 activation. Resveratrol reduced phosphorylation of ribosomal protein S6 and the mTOR inhibitor rapamycin further enhanced resveratrol-induced cell death. These results suggest that the downregulation of PI3K/Akt/mTOR signaling pathways may be an important mediator in resveratrol-induced apoptosis in glioma cells.
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PMID:Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. 1982 68

The identification of genes involved in carcinogenesis and tumor progression is of great interest since these genes might be feasible as candidates for new tumor-targeted therapy strategies. Chimeric tumor suppressor-1 (CTS-1), an artificial synthetic variant of p53, resists common p53 inactivation and could therefore be defined as a dominant-positive p53 variant. Overexpression of CTS-1 induces caspase-independent cell death. We used whole-genome microarray expression analysis in a parental (229(P)) and a CTS-1-resistant glioma cell line (229(Res)) to analyze alterations in gene expression in Ad-CTS-1-infected and in uninfected parental and resistant cells. In total, 700 genes were differentially expressed in infected and 313 genes in uninfected 229(Res) versus 229(P) cells. Ingenuity Pathway Analysis determined a variety of differentially expressed genes in Ad-CTS-1-infected cells that were members of intracellular networks with central tumor-involved players such as nuclear factor-kappaB (NFkappaB), protein kinase B/AKT or transforming growth factor-beta. Here we focused on the function of NFkappaB in Ad-CTS-1-mediated cell death in glioma. NFkappaB was activated in Ad-CTS-1-infected 229(P) but not 229(Res) cells. NFkappaB activation was accompanied by the induction of cell death in parental cells. Inhibition of NFkappaB activity by expression of an IkappaB super repressor or upregulation of the NFkappaB-linked gene Bex protected parental cells to Ad-CTS-1-induced cell death, whereas knockdown of Bex sensitized both parental and resistant cells. Taken together, these data suggest that activation of the normally antiapoptotic protein NFkappaB does not always necessarily protect cells from apoptosis but, in the glioma cell lines tested so far, and in an environment where p53 is constitutively active, also leads to the induction of cell death.
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PMID:Gene expression profile in a glioma cell line resistant to cell death induced by the chimeric tumor suppressor-1 (CTS-1), a dominant-positive variant of p53--the role of NFkappaB. 2001 65


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