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

FTY720, a metabolite from Isaria sinclairii, has been developed to be a potent immunosuppressive drug with induction of apoptosis in T cells and several cell lines. We investigated whether FTY720 induces apoptosis in human glioma cell lines, since they are relatively resistant to multiple apoptotic stimuli. In human glioma cells including T98G, FTY720 induced apoptosiswith ED50 between 1 to 10 microg/ml, while etoposidedid not induce apoptosis at the same doses. Among the caspase family proteases, mainly caspase-6 was activated during the apoptosis by FTY720 but not etoposide. In addition, FTY720 caused tyrosine dephosphorylation of FAK and did not activate a FAK-PI3-kinase survival pathway. This was confirmed also by the observation that orthovanadate prevented FTY720-induced dephosphorylation of FAK and inhibited FTY720-induced cell death. We assumed that FTY720 induced FAK dephosphorylation and cut off the FAK-PI3-kinase pathway resulting in the induction of apoptosis via caspase-6 activation in these glioma cells.
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PMID:FTY720, a novel immunosuppressive agent, induces apoptosis in human glioma cells. 1118 Oct 42

We have established that focal adhesion kinase (FAK)-transfected HL-60 (HL-60/FAK) cells were highly resistant to hydrogen peroxide and etoposide-induced apoptosis compared to vector-transfected cells. Mutagenesis study revealed that Y397 is required for anti-apoptotic activity in HL-60/FAK, since Y397F-mutated FAK (397FAK) lost anti-apoptotic function. Assuming that 397FAK functions as a dominant negative FAK, we introduced 397FAK cDNA into a human glioma cell line, T98G, using an adenoviral vector. We found that 397FAK induced marked apoptosis with significant FAK degradation. As PI3-kinase-Akt survival pathway was constitutively activated in T98G cells, we hypothesized that this pathway was shut off by 397FAK gene transfection. As expected, activation of PI3-kinase-Akt survival pathway was decreased by the 397FAK gene transfection. 397FAK activated mainly caspase-6 which induced degradation of transfected FAK as well as endogenous FAK. These results indicated that 397FAK induces apoptosis in T98G cells, by interrupting signals of FAK leading to the survival pathway in T98G glioma cells.
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PMID:Mutated focal adhesion kinase induces apoptosis in a human glioma cell line, T98G. 1205 81

Gliomas are a large collection of primary central nervous system tumors that arise from glia, astrocytes and oligodendrocytes or their precursors. They are graded on a scale of I to IV based on their degree of malignancy as judged by variable histological features. Genetic and biochemical evidences have proven that gliomagenesis involves a stepwise accumulation of genetic lesions affecting either signal transduction pathways activated by receptor tyrosine kinases (RTKs) or cell cycle growth arrest pathways. Many of these observed molecular alterations are now being used to compliment clinical diagnosis. Genetic alterations affecting RTK signaling results in the activation of several downstream pathways, such as the PI3-kinase/Akt and Ras/Raf/MEK/MAPK pathways, which provides a number of novel targets for glioma therapy. This article aims to present a broad understanding of the receptor tyrosine kinase signaling networks involved in gliomagenesis. Molecular classification of primary glial tumors and elucidation of cooperative interactions between different genetic lesions will eventually allow us to target distinct glioma subsets and will provide a more rational approach to adjuvant therapies for this refractory disease.
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PMID:Receptor tyrosine kinase signaling in gliomagenesis: pathobiology and therapeutic approaches. 1450 1

Loss of phosphatase and tensin homolog (PTEN) and amplification of the epidermal growth factor receptor (EGFR) gene contribute to the progression of gliomas. As downstream targets of the PTEN and EGFR signaling pathways, Akt, NFkappaB, and signal transducer and activator of transcription-3 (Stat3) have been shown to play important roles in the control of cell proliferation, apoptosis, and oncogenesis. We examined the activation status of Akt, NFkappaB, and Stat3 in 259 diffuse gliomas using tissue microarrays and immunohistochemistry, and evaluated their association with glioma grade. We observed significant positive correlations between the activation status of Akt and NFkappaB and glioma grade. In contrast, only focal immunoreactivity for phospho-Stat3 was observed in < 9% of high-grade gliomas. In addition, we observed a significant correlation between the activation of Akt and NFkappaB. Functional correlation between Akt activation and the activation of NFkappaB was confirmed in U251MG GBM cells in which inhibition of Akt activation either by stable expression of PTEN or by the PI3-kinase inhibitors, wortmannin and LY294002, led to a concomitant decrease in NFkappaB-binding activity. Thus, our results demonstrate that constitutive activation of Akt and NFkappaB, but not Stat3, contributes significantly to the progression of diffuse gliomas, and activation of Akt may lead to NFkappaB activation in high-grade gliomas.
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PMID:Analysis of the activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas. 1518 9

PTEN is a tumor suppressor gene whose loss of function is observed in approximately 40-50% of human cancers. Although insulin-like growth factor binding protein-2 (IGFBP-2) was classically described as a growth inhibitor, multiple recent reports have shown an association of overexpression and/or high serum levels of IGFBP-2 with poor prognosis of several malignancies, including gliomas. Using an inducible PTEN expression system in the PTEN-null glioma cell line U251, we demonstrate that PTEN-induction is associated with reduced proliferation, increased apoptosis, and a substantial reduction of the high levels of IGFBP-2 expression. The PTEN-induced decrease in IGFBP-2 expression could be mimicked with the PI3-kinase inhibitor LY294002, indicating that the lipid phosphatase activity of PTEN is responsible for the observed effect. However, the rapamycin analog CCI-779 did not affect IGFBP-2 expression, suggesting that the PTEN-induced decrease in IGFBP-2 expression is not attributable to decreased mTOR signalling. Recombinant human IGFBP-2 was unable to rescue U251-PTEN cells from the antiproliferative effects of PTEN, and IGFBP-2 siRNA did not affect the IGF-dependent or -independent growth of this cell line. These results suggest that the clinical data linking IGFBP-2 expression to poor prognosis may arise, at least in part, because high levels of IGFBP-2 expression correlate with loss of function of PTEN, which is well known to lead to aggressive behavior of gliomas. Our results motivate translational research regarding the relationship between IGFBP-2 expression and loss of function of PTEN.
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PMID:PTEN-induction in U251 glioma cells decreases the expression of insulin-like growth factor binding protein-2. 1615 32

The continual activation of signaling cascades results in dramatic consequences that include loss of cellular growth control and neoplastic transformation. We show here that phosphoinositide 3-kinase and its mediator Akt was constitutively activated in glioma and that this might be due to the aberrant expression of their natural antagonist PTEN. The PTEN (phosphatase and tensin homologue deleted on chromosome ten) tumor suppressor gene modulates cell growth and survival through mechanisms that are incompletely understood. In this study, we investigated the possibility that PTEN mediates its effects through modulation of transcription factor AP-1, which is in part due to decrease in c-fos expression which was dependent on PI3kinase activity. Consistent with a reduction in the c-fos levels, an AP-1 dependent reporter gene was poorly induced in the PTEN expressing cell lines. In contrast to its effect on c-fos, PTEN did not affect the expression of c-Jun and other fos family members. We also show that the effect of PTEN on c-fos expression was due to its ability to antagonize PI3-kinase and could be mimicked by the expression of dominant negative Akt mutant. Taken together, these data indicate that the aberrant expression of PTEN contributes to the activation of the PI3kinase/Akt pathway and its transcription factor mediators in glioma. We conclude that the ectopic expression of PTEN down regulates the proliferation of glioma cells through the suppression of AP-1 and that this target might be essential for its central role in the growth and survival of glioma cancer cells.
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PMID:PTEN down regulates AP-1 and targets c-fos in human glioma cells via PI3-kinase/Akt pathway. 1723 55

B7 homolog 1 (B7-H1) is a recently discovered immunoresistance protein that is regulated posttranscriptionally after PTEN loss in malignant glioma, a deadly form of brain tumor. Here, the impact of gamma-interferon-mediated activation of B7-H1 was investigated in glioblastoma patients with PTEN loss. Lymphocytes and T cells were selected for apoptosis assays after 1 : 1 coculture with autologous glioma cells. Gamma interferon treatment of PTEN-deficient tumors resulted in superinduction of B7-H1 protein that correlated with increased T-cell apoptosis, an effect dependent upon activation of the PI3-kinase pathway. The combination of PTEN loss and gamma-interferon exposure in glioblastoma patients results in an exceptionally immunoresistant phenotype that may negate adaptive immunity through induction of T-cell apoptosis.
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PMID:Gamma interferon-mediated superinduction of B7-H1 in PTEN-deficient glioblastoma: a paradoxical mechanism of immune evasion. 1987 77

Prostaglandin E(2) (PGE(2)) plays a critical role in influencing the biological behavior of tumor cells. We previously demonstrated that PGE(2) stimulates human glioma cell growth via activation of protein kinase A (PKA) type II. This study was undertaken to further elucidate the intracellular pathways activated by PGE(2) downstream to PKA. Stimulation of U87-MG glioma cells with PGE(2) increased phosphorylation of the cyclic-AMP response element (CRE) binding protein CREB at Ser-133 and CREB-driven transcription in a dose- and time-dependent manner. Expression of dominant CREB constructs that interfere with CREB phosphorylation at Ser-133 or with its binding to the CRE site markedly decreased PGE(2)-induced CREB activation. Inhibition of PKA by H-89 or expression of a dominant negative PKA construct attenuated PGE(2)-induced CREB activation. Moreover, inhibition of PKA type II decreased PGE(2)-induced CREB-dependent transcription by 45% compared to vehicle-treated cells. To investigate the involvement of additional signaling pathways, U87-MG cells were pretreated with wortmannin or LY294002 to inhibit the PI3-kinase/AKT pathway. Both inhibitors had no effect on PGE(2)-induced CREB phosphorylation and transcriptional activity, suggesting that PGE(2) activates CREB in a PI3-kinase/AKT independent manner. Challenge of U87-MG cells with PGE(2), at concentrations that induced maximal CREB activation, or with forskolin inhibited extracellular signal-regulated kinase (ERK) phosphorylation. Pretreatment of U87-MG cells with the ERK inhibitor PD98059, accentuated ERK inhibition and increased CREB phosphorylation at Ser-133 and CREB-driven transcription stimulated by PGE(2), suggesting that inhibition of ERK contributes to PGE(2)-induced CREB activation. Inhibition of ERK by PGE(2) or by forskolin was rescued by treatment of cells with H-89 or by the dominant negative PKA construct. Moreover, PGE(2) or forskolin inhibited phosphorylation of Raf-1 phosphorylation at Ser-338. Challenge of U87-MG cells with 11-deoxy-PGE(1) increased CREB-driven transcription and stimulated cell growth, while other PGE(2) analogues had no effect. Together our results reveal a novel signaling pathway whereby PGE(2) signals through PKA to inhibit ERK and increase CREB transcriptional activity.
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PMID:Prostaglandin E2 activates cAMP response element-binding protein in glioma cells via a signaling pathway involving PKA-dependent inhibition of ERK. 2001 75

The resistance of glioma cells to a number of antitumor agents and the highly invasive nature of glioma cells that escape the primary tumor mass are key impediments to the eradication of tumors in glioma patients. In this study, we evaluated the therapeutic efficacy of a novel PI3-kinase/mTOR inhibitor, PI-103, in established glioma lines and primary CD133(+) glioma-initiating cells and explored the potential of combining PI-103 with stem cell-delivered secretable tumor necrosis factor apoptosis-inducing ligand (S-TRAIL) both in vitro and in orthotopic mouse models of gliomas. We show that PI-103 inhibits proliferation and invasion, causes G(0)-G(1) arrest in cell cycle, and results in significant attenuation of orthotopic tumor growth in vivo. Establishing cocultures of neural stem cells (NSC) and glioma cells, we show that PI-103 augments the response of glioma cells to stem cell-delivered S-TRAIL. Using bimodal optical imaging, we show that when different regimens of systemic PI-103 delivery are combined with NSC-derived S-TRAIL, a significant reduction in tumor volumes is observed compared with PI-103 treatment alone. To our knowledge, this is the first study that reveals the antitumor effect of PI-103 in intracranial gliomas. Our findings offer a preclinical rationale for application of mechanism-based systemically delivered antiproliferative agents and novel stem cell-based proapoptotic therapies to improve treatment of malignant gliomas.
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PMID:A dual PI3K/mTOR inhibitor, PI-103, cooperates with stem cell-delivered TRAIL in experimental glioma models. 2108 67

The identification of mammalian target of rapamycin (mTOR) as a major mediator of neurofibromatosis-1 (NF1) tumor growth has led to the initiation of clinical trials using rapamycin analogs. Previous studies from our laboratory have shown that durable responses to rapamycin treatment in a genetically engineered mouse model of Nf1 optic glioma require 20 mg/kg/day, whereas only transient tumor growth suppression was observed with 5 mg/kg/day rapamycin despite complete silencing of ribosomal S6 activity. To gain clinically relevant insights into the mechanism underlying this dose-dependent effect, we used Nf1-deficient glial cells in vitro and in vivo. First, there was an exponential relationship between blood and brain rapamycin levels. Second, we show that currently used biomarkers of mTOR pathway inhibition (phospho-S6, phospho-4EBP1, phospho-STAT3, and Jagged-1 levels) and tumor proliferation (Ki67) do not accurately reflect mTOR target inhibition or Nf1-deficient glial growth suppression. Third, the incomplete suppression of Nf1-deficient glial cell proliferation in vivo following 5 mg/kg/day rapamycin treatment reflects mTOR-mediated AKT activation, such that combined 5 mg/kg/day rapamycin and PI3-kinase (PI3K) inhibition or dual PI3K/mTOR inhibition recapitulates the growth suppressive effects of 20 mg/kg/day rapamycin. These new findings argue for the identification of more accurate biomarkers for rapamycin treatment response and provide reference preclinical data for comparing human rapamycin levels with target effects in the brain.
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PMID:Interpreting mammalian target of rapamycin and cell growth inhibition in a genetically engineered mouse model of Nf1-deficient astrocytes. 2121 28


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