Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously proposed that intravascular thrombosis and subsequent vasoocclusion contribute to the development of pseudopalisading necrosis, a pathologic hallmark that distinguishes glioblastoma (WHO grade 4) from lower grade astrocytomas. To better understand the potential prothrombotic mechanisms underlying the formation of these structures that drive tumor angiogenesis, we investigated tissue factor (TF), a potent procoagulant protein known to be overexpressed in astrocytomas. We hypothesized that PTEN loss and tumor hypoxia, which characterize glioblastoma but not lower grade astrocytomas, could up-regulate TF expression and cause intravascular thrombotic occlusion. We examined the effect of PTEN restoration and hypoxia on TF expression and plasma coagulation using a human glioma cell line containing an inducible wt-PTEN cDNA. Cell exposure to hypoxia (1% O(2)) markedly increased TF expression, whereas restoration of wt-PTEN caused decreased cellular TF. The latter effect was at least partially dependent on PTEN's protein phosphatase activity. Hypoxic cells accelerated plasma clotting in tilt tube assays and this effect was prevented by both inhibitory antibodies to TF and plasma lacking factor VII, implicating TF-dependent mechanisms. To further examine the genetic events leading to TF up-regulation during progression of astrocytomas, we investigated its expression in a series of human astrocytes sequentially infected with E6/E7/human telomerase, Ras, and Akt. Cells transformed with Akt showed the greatest incremental increase in hypoxia-induced TF expression and secretion. Together, our results show that PTEN loss and hypoxia up-regulate TF expression and promote plasma clotting by glioma cells, suggesting that these mechanisms may underlie intravascular thrombosis and pseudopalisading necrosis in glioblastoma.
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PMID:PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. 1573 28

Akt/protein kinase B critically regulates the balance between cell survival and apoptosis. Phosphorylation of Akt at two key sites, the activation loop and the hydrophobic motif, activates the kinase and promotes cell survival. The mechanism of dephosphorylation and signal termination is unknown. Here, we identify a protein phosphatase, PH domain leucine-rich repeat protein phosphatase (PHLPP), that specifically dephosphorylates the hydrophobic motif of Akt (Ser473 in Akt1), triggering apoptosis and suppressing tumor growth. The effects of PHLPP on apoptosis are prevented in cells expressing an S473D construct of Akt, revealing that the hydrophobic motif is the primary cellular target of PHLPP. PHLPP levels are markedly reduced in several colon cancer and glioblastoma cell lines that have elevated Akt phosphorylation. Reintroduction of PHLPP into a glioblastoma cell line causes a dramatic suppression of tumor growth. These data are consistent with PHLPP terminating Akt signaling by directly dephosphorylating and inactivating Akt.
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PMID:PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. 1583 16

PTEN is a major tumor suppressor gene that has been shown to inhibit cell invasion. Its mutation has been found in 20-40% of malignant gliomas. Meanwhile, the type III EGFR mutation (EGFRvIII), which was frequently found in gliomas, promoted cell invasion. In the present study, the effects of PTEN on cell invasion were investigated in U87DeltaEGFR glioblastoma cells with EGFRvIII expression but missing PTEN. The cell invasion was downregulated by transfection of phosphatase-active forms of PTEN (wild-type and G129E) but not by PTEN (C124A) with an inactive phosphatase domain; the effects were correlated with decreased tyrosine phosphatase levels of FAK at Tyr397, which was increased by EGFRvIII. Overexpression of FAK mutant (Y397F) could partially mimic the effect of PTEN on cell invasion. Although EGFRvIII increased the levels of P-Akt and PTEN eliminated it, PI-3K inhibitors, wortmannin or Ly294002, could not decrease the cell invasion. In conclusion, PTEN could inhibit cell invasion even in the presence of the constitutively active EGFR; this inhibition depended on its protein phosphatase activity, partially by dephosphorylating FAK, but not depended on its lipid phosphatase activity.
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PMID:Protein phosphatase activity of PTEN inhibited the invasion of glioma cells with epidermal growth factor receptor mutation type III expression. 1598 32

Despite advances in understanding the role of histone deacetylases (HDACs) in tumorigenesis, the mechanism by which HDAC inhibitors mediate antineoplastic effects remains elusive. Modifications of the histone code alone are not sufficient to account for the antitumor effect of HDAC inhibitors. The present study demonstrates a novel histone acetylation-independent mechanism by which HDAC inhibitors cause Akt dephosphorylation in U87MG glioblastoma and PC-3 prostate cancer cells by disrupting HDAC-protein phosphatase 1 (PP1) complexes. Of four HDAC inhibitors examined, trichostatin A (TSA) and HDAC42 exhibit the highest activity in down-regulating phospho-Akt, followed by suberoylanilide hydroxamic acid, whereas MS-275 shows only a marginal effect at 5 microm. This differential potency parallels the respective activities in inducing tubulin acetylation, a non-histone substrate for HDAC6. Evidence indicates that this Akt dephosphorylation is not mediated through deactivation of upstream kinases or activation of downstream phosphatases. However, the effect of TSA on phospho-Akt can be rescued by PP1 inhibition but not that of protein phosphatase 2A. Immunochemical analyses reveal that TSA blocks specific interactions of PP1 with HDACs 1 and 6, resulting in increased PP1-Akt association. Moreover, we used isozyme-specific small interfering RNAs to confirm the role of HDACs 1 and 6 as key mediators in facilitating Akt dephosphorylation. The selective action of HDAC inhibitors on HDAC-PP1 complexes represents the first example of modulating specific PP1 interactions by small molecule agents. From a clinical perspective, identification of this PP1-facilitated dephosphorylation mechanism underscores the potential use of HDAC inhibitors in lowering the apoptosis threshold for other therapeutic agents through Akt down-regulation.
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PMID:Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes. 1618 12

The phosphatase and tensin homolog tumor suppressor (PTEN) belongs to a class of "gatekeeper" tumor suppressors together with p53, retinoblastoma and adenomatous polyposis. It is considered one of the most important tumor suppressors in the post p53 era. Previously to identify the molecules involved in the signaling network regulated by PTEN using proteomic tools, we reported global proteome profiles at different time points using the PTEN inducible NIH3T3 cells (Kim, S.-y., Kim, Y. S., Bahk, Y. Y., Mol. Cells 2003, 15, 396-405). However, the system had a critical limitation that NIH3T3 cell has endogenous wild-type PTEN and, thus to be exact, the induced PTEN could not give the answer about the real physiological roles of this tumor suppressor. Here, to find out PTEN-related protein network we have established various PTEN (wild-type, an activity inert C124G, and a lipid phosphatase deficient G129E)-expressing cell clones in U-87 MG human glioblastoma cells lacking detectable PTEN as a result of genetic lesions. In this biological context, we compared their morphological and expression patterns, and proteome images of each PTEN-expressing cell clone by 2-DE followed by identification with MALDI-TOF MS. We obtained some pieces of evidence that morphological change by PTEN expression is mediated by its protein phosphatase activity and their growth rate by the lipid phosphatase activity. The proteomic approaches showed that 30 proteins possibly correlated with PTEN's protein phosphatase activity (13 down-regulated and 17 up-regulated) and 20 with the lipid phosphatase activity (14 down-regulated and 6 up-regulated) were identified. Taken together, we conclude that the comparative analysis of proteome from various PTEN-expressing cells has yielded interpretable data to elucidate the protein network directly and/or indirectly caused by individual phosphatase activities of PTEN in vivo.
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PMID:Proteome profile changes that are differentially regulated by lipid and protein phosphatase activities of tumor suppressor PTEN in PTEN-expressing U-87 MG human glioblastoma cells. 1629 7

The challenging possibility of selectively inducing mitotic death in tumor cells by combining genotoxic agents with the inhibition of G2 checkpoints of the cell cycle is the subject of intensive investigation. We show that very low concentrations (3.5 and 5 nM) of okadaic acid induce mitotic death in two glioblastoma cell lines, in the absence of genotoxic agents. At the concentrations used, the main target of okadaic acid action is protein phosphatase 2A (PP2A), an enzyme deeply involved in the negative control of cell-cycle progression. The peculiar susceptibility of glioblastoma cells to induction of mitotic death by very low concentrations of okadaic acid must be related to an impairment of PP2A activity and to a specific deficiency in some cell-cycle checkpoints. In addition to its ability to induce abnormal mitoses in actively proliferating glioblastoma cells, okadaic acid possesses the ability to force semi-confluent glioblastoma cells to the M phase of the cell cycle, where they show the same abnormalities observed in actively proliferating glioblastoma cells. In semi-confluent cells the induction of mitotic death involves the activity of both the extracellular signal regulated kinases (ERKs) and the M-phase promoting factor: okadaic acid overstimulates ERK activity, and PD98059 (inhibitor of ERK activation) as well as roscovitine (S)-isomer (specific inhibitor of M-phase promoting factor activity) counteract the induction of mitotic death. Our results show that, without the use of genotoxic agents, it is possible to induce mitotic death in glioblastoma cells by activating the same uncontrolled pathways responsible for the uncontrolled proliferation.
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PMID:GL15 and U251 glioblastoma-derived human cell lines are peculiarly susceptible to induction of mitotic death by very low concentrations of okadaic acid. 1639 70

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

Down syndrome candidate region 1 (DSCR1), an endogenous inhibitor of calcineurin, inhibits the expression of genes involved in the inflammatory response. To elucidate the molecular basis of these anti-inflammatory effects, we analyzed the role of DSCR1 in the regulation of NF-kappaB transactivation using glioblastoma cells stably transfected with DSCR1.4 or its truncation mutants (DSCR1.4-(1-133) and DSCR1.4-(134-197)). Overexpression of DSCR1.4 significantly attenuated the induction of cyclooxygenase-2 (COX-2) expression by phorbol 12-myristate 13-acetate (PMA) via a calcineurin-independent mechanism. Experiments using inhibitors of the signaling molecules for NF-kappaB activation showed that NF-kappaB is responsible for the induction of COX-2. Full-length and truncated DSCR1.4 decreased the steady-state activity of NF-kappaB as well as PMA-induced activation of NF-kappaB, which correlated with attenuation of COX-2 induction. DSCR1.4 did not affect the PMA-stimulated phosphorylation or degradation kinetics of IkappaBalpha; however, DSCR1.4 significantly decreased the basal turnover rate of IkappaBalpha and consequently up-regulated its steady-state level. In the same context, knockdown of endogenous DSCR1.4 increased the turnover rate of IkappaBalpha as well as COX-2 induction. These results suggest that DSCR1 attenuates NF-kappaB-mediated transcriptional activation by stabilizing its inhibitory protein, IkappaBalpha.
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PMID:Down syndrome candidate region 1 increases the stability of the IkappaBalpha protein: implications for its anti-inflammatory effects. 1706 74

Doublecortin (DCX) is one of the three genes found from Affymetrix gene chip analysis related to glioma patient survival. Two other genes (e.g., osteonectin and semaphorin 3B) are well characterized as antioncogenic and tumor suppressor genes. However, there is no report about the involvement of DCX in cancer. Here, we show that gene transfer technology into DCX-deficient glioblastoma cell lines, such as A172, U87, U251N, RG2, and 9L, with DCX cDNA significantly suppressed growth of these glioma cells. U87 cells with ectopic expression of DCX exhibit a marked suppression of the transformed phenotype as growth arrested in the G(2) phase of the cell cycle progression, small colony formation in soft agar, and no tumor formation in nude rats. This transformed phenotype can be restored by knocking down DCX expression with DCX small interfering RNA. DCX was highly phosphorylated in glioma cells. Phosphorylation in the glioma cells was greater than in noncancer cells such as mouse NIH 3T3 and human embryonic kidney 293T cells. Coimmunoprecipitation of the phosphorylated DCX and spinophilin/neurabin II from DCX-synthesizing glioma cells indicated their interaction. This interaction would lead to a block of anchorage-independent growth as neurabin II is a synergistic inhibitor of anchorage-independent growth with p14ARF (ARF). Interaction between phosphorylated DCX and neurabin II may induce the association of the protein phosphatase 1 catalytic subunit (PP1) with neurabin II and inactivate PP1 and block mitosis during G(2) and M phases of the cell cycle progression. Thus, DCX seems to be a tumor suppressor of glioma.
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PMID:Ectopic doublecortin gene expression suppresses the malignant phenotype in glioblastoma cells. 1717 68

Glioblastoma is the deadliest and most prevalent brain tumor, which is not yet amenable to any treatments. Therefore, new and innovative therapeutic strategies need to be developed for treating this deadly disease. We found that all-trans retinoic acid (ATRA) or 13-cis retinoic acid (13-CRA) induced astrocytic differentiation with down regulation of telomerase activity in rat glioblastoma C6 cells and enhanced sensitivity of the cells to interferon-gamma (IFN-gamma) or taxol (TXL) for apoptosis. Sensitivity of differentiated cells to IFN-gamma or TXL was greatly increased for apoptosis with increases in calcineurin expression, Bax:Bcl-2 ratio, mitochondrial release of cytochrome c, and expression and activity of calpain and caspases. Treatment with IFN-gamma activated caspase-8 indicating induction of apoptosis via the receptor-mediated pathway. Notably, IFN-gamma activated the signal transducer and activator of transcription-1 (STAT-1) for signaling via binding to gamma activator sequence (GAS), whereas TXL activated Raf-1 kinase for inactivation of Bcl-2 by its phosphorylation. We confirmed involvement of different proteolytic mechanisms in cell death by pretreating the cells with caspase-8 inhibitor II, calpeptin (calpain inhibitor), and caspase-9 inhibitor I, and caspase-3 inhibitor IV. Results demonstrated that retinoids induced astrocytic differentiation with down regulation of telomerase activity and worked synergistically to enhance sensitivity of cells to the cytotoxic agent IFN-gamma and the cytostatic agent TXL for apoptosis. This combination therapy for differentiation and apoptosis could be highly effective for controlling the malignant growth of glioblastoma.
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PMID:Differentiation decreased telomerase activity in rat glioblastoma C6 cells and increased sensitivity to IFN-gamma and taxol for apoptosis. 1769 33


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