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)

Therapeutic inhibition of mammalian target of rapamycin (mTOR) in cancer is complicated by the existence of a negative feedback loop linking mTOR to the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Thus, mTOR inhibition by rapamycin or TSC1/2 results in increased PI3K-Akt activation. The death domain kinase receptor interacting protein 1 (RIP1) plays a key role in nuclear factor-kappaB (NF-kappaB) activation and also activates the PI3K-Akt pathway through unknown mechanisms. RIP1 has recently been found to be overexpressed in glioblastoma multiforme, the most common adult primary malignant brain tumor, but not in grade II to III glioma. Our data suggest that RIP1 activates PI3K-Akt using dual mechanisms by removing the two major brakes on PI3K-Akt activity. First, increased expression of RIP1 activates PI3K-Akt by interrupting the mTOR negative feedback loop. However, unlike other signals that regulate mTOR activity without affecting its level, RIP1 negatively regulates mTOR transcription via a NF-kappaB-dependent mechanism. The second mechanism used by RIP1 to activate PI3K-Akt is down-regulation of cellular PTEN levels, which appears to be independent of NF-kappaB activation. The clinical relevance of these findings is highlighted by the demonstration that RIP1 levels correlate with activation of Akt in glioblastoma multiforme. Thus, our study shows that RIP1 regulates key components of the PTEN-PI3K-Akt-mTOR pathway and elucidates a novel negative regulation of mTOR signaling at the transcriptional level by the NF-kappaB pathway. Our data suggest that the RIP1-NF-kappaB status of tumors may influence response to treatments targeting the PTEN-PI3K-mTOR signaling axis.
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PMID:RIP1 activates PI3K-Akt via a dual mechanism involving NF-kappaB-mediated inhibition of the mTOR-S6K-IRS1 negative feedback loop and down-regulation of PTEN. 1943 90

Glioblastoma multiforme (GBM) is the most lethal of brain tumors and is highly resistant to ionizing radiation (IR) and chemotherapy. Here, we report on a molecular mechanism by which a key glioma-specific mutation, epidermal growth factor receptor variant III (EGFRvIII), confers radiation resistance. Using Ink4a/Arf-deficient primary mouse astrocytes, primary astrocytes immortalized by p53/Rb suppression, as well as human U87 glioma cells, we show that EGFRvIII expression enhances clonogenic survival following IR. This enhanced radioresistance is due to accelerated repair of DNA double-strand breaks (DSB), the most lethal lesion inflicted by IR. The EGFR inhibitor gefitinib (Iressa) and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 attenuate the rate of DSB repair. Importantly, expression of constitutively active, myristylated Akt-1 accelerates repair, implicating the PI3K/Akt-1 pathway in radioresistance. Most notably, EGFRvIII-expressing U87 glioma cells show elevated activation of a key DSB repair enzyme, DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Enhanced radioresistance is abrogated by the DNA-PKcs-specific inhibitor NU7026, and EGFRvIII fails to confer radioresistance in DNA-PKcs-deficient cells. In vivo, orthotopic U87-EGFRvIII-derived tumors display faster rates of DSB repair following whole-brain radiotherapy compared with U87-derived tumors. Consequently, EGFRvIII-expressing tumors are radioresistant and continue to grow following whole-brain radiotherapy with little effect on overall survival. These in vitro and in vivo data support our hypothesis that EGFRvIII expression promotes DNA-PKcs activation and DSB repair, perhaps as a consequence of hyperactivated PI3K/Akt-1 signaling. Taken together, our results raise the possibility that EGFR and/or DNA-PKcs inhibition concurrent with radiation may be an effective therapeutic strategy for radiosensitizing high-grade gliomas.
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PMID:EGFRvIII and DNA double-strand break repair: a molecular mechanism for radioresistance in glioblastoma. 1943 98

Gliomas are the most common adult primary brain tumors, and the most malignant form, glioblastoma multiforme, is invariably fatal. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is altered in most glioblastoma multiforme. PTEN, an important negative regulator of the PI3K-Akt pathway, is also commonly mutated in glioma, leading to constitutive activation of Akt. One ultimate consequence is phosphorylation and inactivation of FOXO forkhead transcription factors that regulate genes involved in apoptosis, cell cycle arrest, nutrient availability, DNA repair, stress, and angiogenesis. We tested the ability of a mutant FOXO1 factor that is not subject to Akt phosphorylation to overcome dysregulated PI3K-Akt signaling in two PTEN-null glioma cell lines, U87 and U251. Adenovirus-mediated gene transfer of the mutant FOXO1 successfully restored cell cycle arrest and induced cell death in vitro and prolonged survival in vivo in xenograft models of human glioma (33% survival at 1 year of animals bearing U251 tumors). However, U87 were much more resistant than U251 to mutant FOXO1-induced death, showing evidence of increased nuclear export and Akt-independent phosphorylation of FOXO1 at S249. A cyclin-dependent kinase 2 inhibitor decreased phosphorylation of S249 and rendered U87 cells significantly more susceptible to mutant FOXO1-induced death. Our results indicate that targeting FOXO1, which is at the convergence point of several growth factor receptor tyrosine kinase pathways, can effectively induce glioma cell death and inhibit tumor growth. They also highlight the importance of Akt-independent phosphorylation events in the nuclear export of FOXO1.
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PMID:Differential response of glioma cells to FOXO1-directed therapy. 1954 5

Cyclooxygenase-2 (COX-2) and phosphatidylinositol 3-kinase (PI3K)/Akt play a critical role in the formation of many malignant tumors, and have been shown to be important therapeutic targets. In the present study, small hairpin RNA (shRNA) expression constructs that target sequences of human COX-2, Akt1 and PIK3R1 were used to examine the proliferation and invasion inhibition effects on SGC7901 gastric adenocarcinoma cells and U251 glioma cells. Cell growth was inhibited by over 70%, as indicated by a MTT assay, and was accompanied by G1/G0 phase arrest in the shRNA treated group, indicating poor cell growth activities. The number of cells invading through the matrigel in the shRNA treated group were significantly decreased (26.4+/-4.6) compared with that of the control group (105+/-4.0) and the nonsense sequence group (102.5+/-6.4). In addition, the tumor volumes in the SGC7901 subcutaneous nude mouse model treated with shRNA was significantly smaller than those of the control group and nonsense sequence group. When COX-2, Akt1 and PIK3R1 were dramatically downregulated, proliferating cell nuclear antigen (PCNA), CyclinD1 and matrix metalloproteinases (MMP-2, MMP-9) were downregulated, while tissue-inhibitor of metalloproteinase-2 (TIMP-2) and P53 were upregulated. Our results demonstrated that shRNA targeting COX-2, Akt1 and PIK3R1 downregulates their expression significantly in a sequence-specific manner, exerting proliferation and invasion inhibition effects on SGC7901 and U251 cells. In conclusion, our data suggest a novel mechanism for the regulation of malignant tumor cell growth and provide evidence for new combinatory gene therapy for malignant tumors.
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PMID:Inhibitory effects of adenovirus mediated COX-2, Akt1 and PIK3R1 shRNA on the growth of malignant tumor cells in vitro and in vivo. 1963 78

Aberrant genetic alternations in human gliomas, such as amplification of epidermal growth factor receptor, mutation and/or deletion of tumor suppressor gene PTEN, and mutations of PIK3CA, contribute to constitutive activation of the phosphatidylinositol 3-kinase (PI3K) pathway. We investigated the potential antitumor activity of NVP-BEZ235, which is a novel dual PI3K/mammalian target of rapamycin (mTOR) inhibitor in gliomas. The compound suppressed glioma cell proliferation with IC(50) values in the low nanomolar range by specifically inhibiting the activity of target proteins including Akt, S6K1, S6, and 4EBP1 in the PI3K/Akt/mTOR signaling pathway. NVP-BEZ235 treatment of glioma cell lines led to G(1) cell cycle arrest and induced autophagy. Furthermore, expression of the vascular endothelial growth factor (VEGF), which is an important angiogenic modulator in glioma cells, was significantly decreased, suggesting that NVP-BEZ235 may also exert an antiangiogenic effect. Preclinical testing of the therapeutic efficacy of NVP-BEZ235 showed that it significantly prolonged the survival of tumor-bearing animals without causing any obvious toxicity. Tumor extracts harvested from animals after treatment showed that the compound inhibited the activity of target proteins in the PI3K/Akt/mTOR cascade. Immunohistochemical analyses also showed a significant reduction in staining for VEGF von Willebrand factor (factor VIII) in NVP-BEZ235-treated tumor sections compared with controls, further confirming that NVP-BEZ235 has an antiangiogenic effect in vivo. We conclude from these findings that NVP-BEZ235 antagonizes PI3K and mTOR signaling and induces cell cycle arrest, down-regulation of VEGF, and autophagy. These results warrant further development of NVP-BEZ235 for clinical trials for human gliomas or other advanced cancers with altered PI3K/Akt/mTOR signaling.
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PMID:NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. 1967 62

Hypoxia contributes to the progression of a variety of cancers by activating adaptive transcriptional programs that promote cell survival, motility and tumor angiogenesis. Although the importance of hypoxia and subsequent hypoxia-inducible factor-1alpha (HIF-1alpha) activation in tumor angiogenesis is well known, their role in the regulation of glioma-derived stem cells is unclear. In this study, we show that hypoxia (1% oxygen) promotes the self-renewal capacity of CD133-positive human glioma-derived cancer stem cells (CSCs). Propagation of the glioma-derived CSCs in a hypoxic environment also led to the expansion of cells bearing CXCR4 (CD184), CD44(low) and A2B5 surface markers. The enhanced self-renewal activity of the CD133-positive CSCs in hypoxia was preceded by upregulation of HIF-1alpha. Knockdown of HIF-1alpha abrogated the hypoxia-mediated CD133-positive CSC expansion. Inhibition of the phosphatidylinositol 3-kinase(PI3K)-Akt or ERK1/2 pathway reduced the hypoxia-driven CD133 expansion, suggesting that these signaling cascades may modulate the hypoxic response. Finally, CSCs propagated at hypoxia robustly retained the undifferentiated phenotype, whereas CSCs cultured at normoxia did not. These results suggest that response to hypoxia by CSCs involves the activation of HIF-1alpha to enhance the self-renewal activity of CD133-positive cells and to inhibit the induction of CSC differentiation. This study illustrates the importance of the tumor microenvironment in determining cellular behavior.
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PMID:Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. 1971 46

The clarification of mechanisms that negatively regulate the invasive behavior of human glioma cells is of great importance in order to find new methods of treatment. In this study, we have focused on the negative regulation of lysophosphatidic acid (LPA)-induced migration in glioma cells. Using small interference RNA and dominant-negative gene strategies in addition to pharmacological tools, we found that isoproterenol (ISO) and sphingosine-1-phosphate (S1P) negatively but differently regulate the LPA-induced migration. ISO-induced suppression of the migration of glioma cells occurs via beta(2)-adrenergic receptor/cAMP/Epac/Rap1B/inhibition of Rac, whereas S1P has been shown to suppress the migration of the cells through S1P(2) receptor/Rho-mediated down-regulation of Rac1. The expression of tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is required for the inhibitory ISO-induced and Rap1B-mediated actions on the migration, Rac1 activation, and Akt activation in response to LPA. Thus, the PTEN-mediated down-regulation of phosphatidylinositol 3-kinase activity may be involved in the regulation of Rap1B-dependent inhibition of Rac1 activity. These findings suggest that there are at least two distinct inhibitory pathways, which are mediated by the S1P(2) receptor and beta(2)-adrenergic receptor, to control the migratory, hence invasive, behavior of glioma cells.
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PMID:Role of Rap1B and tumor suppressor PTEN in the negative regulation of lysophosphatidic acid--induced migration by isoproterenol in glioma cells. 1986 56

Forkhead box class O 3a (FOXO3a) is an important direct target of the phosphatidylinositol 3-kinase (PI3K)/protein B(Akt) pathway, mediating signal transduction in regulating cell survival and cell-cycle progression. Recent reports have shown that FOXO3a inhibits cell-cycle progression at the G1/S transition by controlling transcription of the cyclin-dependent kinase inhibitor p27(kip1), which is frequently down-regulated in human cancers, including human glioma. In this study we investigated the status of FOXO3a expression and related signaling in human glioma in order to test its potential value as a therapeutic target for this disease. Immunohistochemistry, western blot, RT-PCR, and immunofluorescence staining analysis were performed on specimens from 70 cases of human glioma and on U87MG and T98G glioma cells. Our data showed FOXO3a expression is directly correlated with the malignant grade of glioma. More importantly, low expression of FOXO3a was associated with poor patient outcome. In vitro, FOXO3a modulated the cell cycle by transcriptional regulation of p27(kip1). Administration of the PI3K pharmacological inhibitor LY294002 abrogated this effect by regulating FOXO3a expression and subcellular localization. Our results suggested that FOXO3a may be a favorable independent prognostic indicator of glioma. Gene therapeutic approaches aimed at PI3K or at pharmacological inhibitors of PI3K to down-regulate P-FOXO3a expression could be developed for management of glioma.
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PMID:Clinical and biological significance of forkhead class box O 3a expression in glioma: mediation of glioma malignancy by transcriptional regulation of p27kip1. 1991 Nov 16

Akt, one of the major downstream effectors of phosphatidylinositol 3-kinase, is hyper-expressed and activated in a variety of cancers including glioblastoma. However, the expression profiles of the Akt isoforms Akt1/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma and their functional roles in malignant glioma are not well understood. Therefore, we examined the protein and mRNA expression patterns of Akt isoforms in tissues from human astrocytomas, glioblastomas, and non-neoplastic regions. We also explored the biological role of each Akt isoform in malignant glioma cells using RNA interference-mediated knock-down and the over-expression of plasmid DNA of each isoform. The expression of Akt1 protein and mRNA was similar in glioma and normal control tissues. Although the protein and mRNA level of Akt2 increased with the pathological grade of malignancy, the expression of Akt3 mRNA and protein decreased as the malignancy grade increased. In U87MG, T98G, and TGB cells, the down-regulation of Akt2 or Akt3 by RNA interference reduced the expression of the phosphorylated form of Bad, resulting in the induction of caspase-dependent apoptosis. Akt1 knock-down did not affect cell growth or survival. We first demonstrate that the over-expression of Akt2 or Akt3 down-regulated the expression of the other protein and that endogenous Akt3 protein showed high kinase activity in U87MG cells. Our data suggest that Akt2 and Akt3 play an important role in the viability of human malignant glioma cells. Targeting Akt2 and Akt3 may hold promise for the treatment of patients with gliomas.
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PMID:Akt2 and Akt3 play a pivotal role in malignant gliomas. 2016 10

Individuals with the neurofibromatosis type 1 (NF1) inherited cancer syndrome exhibit neuronal dysfunction that predominantly affects the CNS. In this report, we demonstrate a unique vulnerability of CNS neurons, but not peripheral nervous system (PNS) neurons, to reduced Nf1 gene expression. Unlike dorsal root ganglion neurons, Nf1 heterozygous (Nf1+/-) hippocampal and retinal ganglion cell (RGC) neurons have decreased growth cone areas and neurite lengths, and increased apoptosis compared to their wild-type counterparts. These abnormal Nf1+/- CNS neuronal phenotypes do not reflect Ras pathway hyperactivation, but rather result from impaired neurofibromin-mediated cAMP generation. In this regard, elevating cAMP levels with forskolin or rolipram treatment, but not MEK (MAP kinase kinase) or PI3-K (phosphatidylinositol 3-kinase) inhibition, reverses these abnormalities to wild-type levels in vitro. In addition, Nf1+/- CNS, but not PNS, neurons exhibit increased apoptosis in response to excitotoxic or oxidative stress in vitro. Since children with NF1-associated optic gliomas often develop visual loss and Nf1 genetically engineered mice with optic glioma exhibit RGC neuronal apoptosis in vivo, we further demonstrate that RGC apoptosis resulting from optic glioma in Nf1 genetically engineered mice is attenuated by rolipram treatment in vivo. Similar to optic glioma-induced RGC apoptosis, the increased RGC neuronal death in Nf1+/- mice after optic nerve crush injury is also attenuated by rolipram treatment in vivo. Together, these findings establish a distinctive role for neurofibromin in CNS neurons with respect to vulnerability to injury, define a CNS-specific neurofibromin intracellular signaling pathway responsible for neuronal survival, and lay the foundation for future neuroprotective glioma treatment approaches.
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PMID:Defective cAMP generation underlies the sensitivity of CNS neurons to neurofibromatosis-1 heterozygosity. 2041 Jan 11


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