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)

Most glioblastoma-derived cell lines express an 8.3 kb ros1 transcript and a 280 kD glycoprotein designated gp280ros1, which can be specifically immunoprecipitated with an anti-ROS antibody. This 280 kD protein possesses in vitro autokinase activity and was observed in four independent glioblastoma cell lines. In a fifth glioblastoma cell line, U-118 MG, a smaller ros1 transcript of 4.0 kb was observed. Immunoprecipitation analysis reveals that the U-118 MG expressed a smaller, 116 kD ros1 gene product. cDNA cloning and sequencing of the U-118 MG ros1 transcript indicates it encodes the entire tyrosine kinase domain and two amino acids of the transmembrane domain of ros1 at its 3' end. Sequences at its 5' end likely arise from another gene.
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PMID:Characterization of the ros1-gene products expressed in human glioblastoma cell lines. 269 58

Activating oncogenic mutations of receptor tyrosine kinases (RTKs) have been reported in several types of cancers. In many cases, genomic rearrangements lead to the fusion of unrelated genes to the DNA coding for the kinase domain of RTKs. All RTK-derived fusion proteins reported so far display oligomerization sequences within the 5' fusion partners that are responsible for oncogenic activation. Here, we report a mechanism by which an altered RTK gains oncogenic potential in a glioblastoma cell line. A microdeletion on 6q21 results in the fusion of FIG, a gene coding for a Golgi apparatus-associated protein, to the kinase domain of the protooncogene c-ROS. The fused protein product FIG-ROS is a potent oncogene, and its transforming potential resides in its ability to interact with and become localized to the Golgi apparatus. Thus we have found a RTK fusion protein whose subcellular location leads to constitutive kinase activation and results in oncogenic transformation.
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PMID:Oncogenic targeting of an activated tyrosine kinase to the Golgi apparatus in a glioblastoma. 1253 61

The transmembrane proto-oncogene receptor tyrosine kinase (RTK) ROS is an orphan receptor that is aberrantly expressed in neoplasms of the central nervous system. Here, we report the fusion of its carboxy-terminal kinase domain to the amino-terminal portion of a protein called FIG (Fused in Glioblastoma) in a human glioblastoma multiforme (GBM). By characterizing both FIG and ROS genes in normal and in U118MG GBM cells, we determined that an intra-chromosomal homozygous deletion of 240 kilobases on 6q21 is responsible for the formation of the FIG-ROS locus. The FIG-ROS transcript is encoded by 7 FIG exons and 9 ROS-derived exons. We also demonstrate that the FIG-ROS locus encodes for an in-frame fusion protein with a constitutively active kinase activity, suggesting that FIG-ROS may act as an oncogene. This is the first example of a fusion RTK protein that results from an intra-chromosomal deletion, and it represents the first fusion RTK protein isolated from a human astrocytoma.
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PMID:Fusion of FIG to the receptor tyrosine kinase ROS in a glioblastoma with an interstitial del(6)(q21q21). 1266 Oct 6

Glioblastoma multiforme is the most common and lethal form of primary brain cancer. Diagnosis of this advanced glioma has a poor prognosis due to the ineffectiveness of current therapies. Aberrant expression of receptor tyrosine kinases (RTK) in glioblastoma multiformes is suggestive of their role in initiation and maintenance of these tumors of the central nervous system. In fact, ectopic expression of the orphan RTK ROS is a frequent event in human brain cancers, yet the pathologic significance of this expression remains undetermined. Here, we show that a glioblastoma-associated, ligand-independent rearrangement product of ROS (FIG-ROS) cooperates with loss of the tumor suppressor gene locus Ink4a;Arf to produce glioblastomas in the mouse. We show that this FIG-ROS-mediated tumor formation in vivo parallels the activation of the tyrosine phosphatase SH2 domain-containing phosphatase-2 (SHP-2) and a phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling axis in tumors and tumor-derived cell lines. We have established a fully penetrant preclinical model for adult onset of glioblastoma multiforme in keeping with major genetic events observed in the human disease. These findings provide novel and important insights into the role of ROS and SHP-2 function in solid tumor biology and set the stage for preclinical testing of targeted therapeutic approaches.
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PMID:ROS fusion tyrosine kinase activates a SH2 domain-containing phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling axis to form glioblastoma in mice. 1688 44

The 18 kDa translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, has been reported to be closely associated with the mitochondrial permeability transition pore (MPTP). TSPO is believed to exert pro-apoptotic functions via modulation of MPTP opening. Cobalt chloride (CoCl(2)), which is sometimes used as a hypoxia mimicking agent, is also known to be able to induce apoptosis. One of our questions was whether CoCl(2) may induce apoptosis via the TSPO. To address this question, we used the U118MG human glioblastoma cell line. We applied the specific TSPO ligand, PK 11195, as well as TSPO knockdown with siRNA and studied their influence on the effects of CoCl(2) on cell death, including activation of the mitochondrial apoptosis pathway. To assay TSPO expression, we applied binding assays and Western blotting to whole cell homogenates and mitochondrial fractions. To assay activation of the mitochondrial apoptosis pathway, including some of the cellular mechanisms involved, we determined the incidence of collapse of the mitochondrial membrane potential (Deltapsi(m)) and cardiolipin oxidation and measured the level of DNA fragmentation to assay apoptotic rates. We found that the TSPO ligand, PK 11195, significantly counteracted induction of cell death by 0.4 mM CoCl(2), including apoptosis, collapse of the Deltapsi(m), and cardiolipin oxidation. Moreover, we found that TSPO knockdown with siRNA fully protected against mentioned cell death mechanisms. Thus, we found that the TSPO is required for cell death induction by CoCl(2), including apoptosis. In conclusion, our studies show that activation of TSPO by CoCl(2) application is required for ROS generation, leading to cardiolipin oxidation, and collapse of the Deltapsi(m), as induced by CoCl(2).
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PMID:CoCl(2) induces apoptosis via the 18 kDa translocator protein in U118MG human glioblastoma cells. 1935 20

We investigated the pro-inflammatory response mediated by TNFalpha in glioblastoma and whether treatment with organoselenium Ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]one) can affect TNFalpha induced inflammatory response. Exposure to TNFalpha increased the expression of pro-inflammatory mediator interleukin IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and cyclooxygenase (COX-2). Treatment with Ebselen abrogated TNFalpha induced increase in pro-inflammatory mediators. Ebselen not only abrogated TNFalpha induced enhanced invasiveness of glioma cells by down-regulating matrix metallo proteinase (MMP-9) and urokinase plasminogen (uPa) activity, but also inhibited glioma cell migration. Treatment with Ebselen also down-regulated the enhanced ROS production of TNFalpha treated glioma cells. In addition, Ebselen induced DNA damage repair signaling response in glioma cells both in the presence and absence of TNFalpha. These studies indicate that together with its known ability to sensitize glioma cell to TNFalpha induced apoptosis, Ebselen can overcome TNFalpha induced pro-inflammatory mediators to prevent a build up of a deleterious pro-inflammatory tumor microenvironment.
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PMID:Ebselen abrogates TNFalpha induced pro-inflammatory response in glioblastoma. 1938 69

In the presence of 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation, an increase in the migration/invasion of U87 glioblastoma cells was detected by a wound healing assay, transwell analysis, and spheroid formation assay by inducing matrix metalloproteinase-9 (MMP-9) enzyme activity via a gelatin zymographic analysis. A dose- and time-dependent increase in cyclooxygenase-2 (COX-2) gene expression with elevated prostaglandin E(2) (PGE(2)) production was identified in TPA- but not in 4alpha-TPA (a respective inactive compound)-treated U87 cells TPA-induced migration/invasion was significantly blocked by adding the COX-2-specific inhibitor, NS398, through a reduction in PGE(2) production. Data from the pharmacological studies using specific chemical inhibitors showed that activation of protein kinase C (PKC) and extracellular signal-regulated kinases (ERKs) was involved in TPA-induced migration/invasion, COX-2 protein expression, and MMP-9 activation. Stimulation of intracellular peroxide production by TPA was detected by a DCHF-DA assay, and the addition of superoxide dismutase (SOD) or tempol significantly inhibited TPA-induced migration/invasion and COX-2 protein expression accompanied by a decrease in peroxide production. An increase in NADPH oxidase activity by TPA was examined, and TPA-induced migration/invasion was blocked by adding DPI, an NADPH oxidase inhibitor. Additionally, the natural flavonoids quercetin (QE), baicalein (BE), and myricetin (ME) effectively blocked TPA-induced migration/invasion while simultaneously inhibiting COX-2/PGE(2) production, MMP-9 enzyme activity, and peroxide production in U87 cells. The contribution of ROS production to the migration/invasion of U87 glioblastoma cells via ERK-activated COX-2/PGE(2) and MMP-9 induction was first investigated here, and agents such as QE, BE, and ME with the ability to block these events possess the potential to be developed for use against migration/invasion by glioblastomas.
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PMID:Contribution of reactive oxygen species to migration/invasion of human glioblastoma cells U87 via ERK-dependent COX-2/PGE(2) activation. 1980 34

Opuntia humifusa, a member of the Cactaceae family widely distributed in the southern regions of the Korean peninsula, has potential bioactive functions and medicinal benefits. In the present study, we investigated the effect of hexane, ethyl acetate extracts and water partitioned fraction of O. humifusa on proliferation, G1 arrest and apoptosis in U87MG human glioblastoma cells. Glioblastoma cellular proliferation was evaluated using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and the effects of O. humifusa partitioned extracts on cell cycle and apoptosis were analyzed by flow cytometry. Our results revealed that when U87MG cells were treated with hexane extracts and water partitioned fraction of O. humifusa, the number of viable cells decreased in a concentration-dependent manner. In addition, water partitioned fractions of O. humifusa induced G1 arrest and non-apoptotic cell death as well as significant increases in ROS production in U87MG cells. In conclusion, water partitioned fractions of O. humifusa induce G1 arrest and inhibit U87MG human glioblastoma cell proliferation.
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PMID:Opuntia humifusa partitioned extracts inhibit the growth of U87MG human glioblastoma cells. 2081 44

The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) has been shown to synergize doxorubicin (Dox) anticancer activity while attenuating its cardiotoxicity. In this study we further explored the selectivity of AN-7's action in several cancer and normal cells treated with anticancer agents. The cells studied were murine mammary 4T1, human breast T47D and glioblastoma U251 cancer cell lines, neonatal rat cardiomyocytes, cardiofibroblasts and astrocytes, and immortalized cardiomyocyte H9C2 cells. Cell death, ROS production and changes in protein expression were measured and in vivo effects were evaluated in Balb-c mice. AN-7 synergized Dox and anti-HER2 cytotoxicity against mammary carcinoma cells with combination indices of 0.74 and 0.79, respectively, while it protected cardiomyocytes against their toxicity. Additionally AN-7 protected astrocytes from Dox-cytoxicity. Cell-type specific changes in the expression of proteins controlling survival, angiogenesis and inflammation by AN-7 or AN-7+Dox were observed. In mice, the protective effect of AN-7 against Dox cardiotoxicity was associated with a reduction in inflammatory factors. In summary, AN-7 augmented the anticancer activity of Dox and anti-HER2 and attenuated their toxicity against normal cells. AN-7 modulation of c-Myc, thrombospondin-1, lo-FGF-2 and other proteins were cell type specific. The effects of AN-7, Dox and their combination were preserved in vivo indicating the potential benefit of combining AN-7 and Dox for clinical use.
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PMID:The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity. 2086 15

Cholangiocarcinoma, also known as bile duct cancer, is the second most common primary hepatic carcinoma with a median survival of less than 2 years. The molecular mechanisms underlying the development of this disease are not clear. To survey activated tyrosine kinases signaling in cholangiocarcinoma, we employed immunoaffinity profiling coupled to mass spectrometry and identified DDR1, EPHA2, EGFR, and ROS tyrosine kinases, along with over 1,000 tyrosine phosphorylation sites from about 750 different proteins in primary cholangiocarcinoma patients. Furthermore, we confirmed the presence of ROS kinase fusions in 8.7% (2 out of 23) of cholangiocarcinoma patients. Expression of the ROS fusions in 3T3 cells confers transforming ability both in vitro and in vivo, and is responsive to its kinase inhibitor. Our data demonstrate that ROS kinase is a promising candidate for a therapeutic target and for a diagnostic molecular marker in cholangiocarcinoma. The identification of ROS tyrosine kinase fusions in cholangiocarcinoma, along with the presence of other ROS kinase fusions in lung cancer and glioblastoma, suggests that a more broadly based screen for activated ROS kinase in cancer is warranted.
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PMID:Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. 2125 78


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