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)

Medulloblastoma (MB) is a primitive neuroectodermal tumor (PNET) of the central nervous system (CNS) and the most common malignant primary brain tumor in children. Currently, poor risk and recurrent MB patients are treated with cytotoxic chemotherapy alone or in combination with surgery and irradiation. In order to improve on therapeutic outcome and reduce toxicity of current treatment strategies, new and novel therapeutic agents are needed for MB patients. To that purpose, we have examined the effect of 2-methoxyestradiol (2-ME), an endogenous non-toxic estrogenic metabolite on the growth of three medulloblastoma cell lines (DAOY, D341 and D283); and two high-grade anaplastic astrocytoma/glioblastoma cell lines, U-87MG and T-98-G. We present evidence to show that 2-ME preferentially inhibits the growth of medulloblastoma cells significantly by blocking cell cycle progression predominantly in G(2)/M phase. 2-ME treatment results in phosphorylation of cdc25C without any significant alterations in the expression of cyclin B1 or p34cdc2. In addition, we observed a decrease in the levels of 14-3-3 proteins following treatment with 2-ME. Furthermore, 2-ME-mediated growth inhibition is accompanied by induction of apoptosis as evidenced by morphological alterations and DNA fragmentation analysis. Of interest is the finding that 2-ME induced apoptosis is not mediated through alterations in the expression of p53 or Bax and that transcriptional activity of NF kappa B and DNA binding activity is reduced indicating that 2-ME disrupts the NF kappa B signaling pathway. These results suggest that 2-ME may prove to be a useful therapeutic agent in the treatment of PNET brain tumors such as medulloblastoma. In addition, as 2-ME inhibits growth predominantly through G(2)/M block, it may enhance the effectiveness of radiation therapy.
Carcinogenesis 2003 Feb
PMID:2-Methoxyestradiol interferes with NF kappa B transcriptional activity in primitive neuroectodermal brain tumors: implications for management. 1258 69

WNT signals play key roles in carcinogenesis and embryogenesis through the specification of cell fate and polarity. Dishevelled proteins are implicated in the WNT - beta-catenin pathway and the WNT-PCP pathway. DAAM1/KIAA0666 is a Dishevelled-binding protein transducing WNT signals to the PCP pathway. Here, we identified and characterized DAAM2 gene by using bioinformatics. Uncharacterized FLJ34430 and KIAA0381 cDNAs were homologous to DAAM1. FLJ34430 was recombined with URB (XM_087331) in the 3'-region, and KIAA0381 was truncated in the 5'-region. Nucleotide sequence of DAAM2 cDNA was determined in silico by adding nucleotide position 1-793 of FLJ34430 onto the 5'-end of KIAA0381. DAAM2 gene consists of 27 exons, and gives rise to four splicing variants due to alternative splicing of alternative promoter type as well as of cassette exon type. DAAM2 gene was linked to the MOCS1 gene on human chromosome 6p21.3 with an interval less than 1 kb. DAAM2 mRNA was expressed in fetal heart, adult hypothalamus, eye, spinal cord, lung, prostate, kidney, and also in glioblastoma, oligodendroglioma, melanoma, mammary adenocarcinoma and chondrosarcoma. DAAM2 was a 1077-amino-acid protein with Formin-homology FH1 and FH2 domains, which showed 68.9% total-amino-acid identity with DAAM1. Among Formin-homology proteins, FDD (Formin-like, Diaphanous, Daam) domain was conserved in FMNL1/FMNL/KW-13, FMNL2/KIAA1902/FHOD2, DIAPH1, DIAPH2, DAAM1 and DAAM2, but not in Fmn1, Fmn2, FHOD1 and Grid2ip. Therefore, it was concluded that FMNL1, FMNL2, DIAPH1, DIAPH2, DAAM1 and DAAM2 proteins constitute the Formin-homology FDD subfamily.
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PMID:Identification and characterization of human DAAM2 gene in silico. 1263 87

Glioblastomas multiforme (GBM) is the most common malignant primary brain tumor in adults. GBM patients have a dismal prognosis, with a median survival of less than 1 year. During the past decade, significant advances have been made in our understanding of the molecular pathogenesis of these tumors. Specific genetic defects have been identified that appear to be important for the development, as well as maintenance of the malignant characteristics that are associated with GBM. Some of these genetic aberrations appear to have prognostic significance. However, even more exciting in this era of molecularly targeted therapy are the clues these gene alterations provide for identifying signaling mechanisms responsible for carcinogenesis, and for identifying potential therapeutic targets. Cancer drug therapy is currently undergoing a major transition with an attempt to move from the use of cytotoxic drugs towards the use of tumor mechanism-based drugs. Advances such as the decoding of the human genome, combinatorial chemistry, and gene expression profiling have led to an increase in the rate at which new drugs are being developed. In this review, we will describe the most common genetic and signaling pathway alterations that have relevance to new drug development for the treatment of GBM.
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PMID:Genetic and signaling pathway alterations in glioblastoma: relevance to novel targeted therapies. 1270 Jan 21

The most severe form of brain glioma, glioblastoma (GBM), is highly malignant and usually resistant to chemotherapy. Therefore, discovery of new targets for gene therapy is important. Using subtraction cloning, we identified the human N-Myc downstream-regulated gene 2 (hNDRG2), located at chromosome 14q11.2, as a gene that is significantly suppressed in GBM tissues. Semiquantitative RT-PCR showed that the hNDRG2 gene transcript is expressed in normal brain tissue and low-grade gliomas but is present at low levels in 15 of 27 (56%) human GBM tissues and all of the 6 human glioblastoma cell lines examined. Furthermore, transfection of human glioblastoma U373 and U138 cells with a cDNA encoding hNDRG2 markedly reduced the cell proliferation. Our findings provide the first evidence to suggest that hNDRG2 may play a role in glioblastoma carcinogenesis.
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PMID:N-Myc downstream-regulated gene 2 (NDRG2) inhibits glioblastoma cell proliferation. 1284 71

A number of recent studies have reported the detection of the ubiquitous human polyomavirus, JC virus (JCV), in samples derived from several types of neural as well as non-neural human tumors. The human neurotropic JCV was first identified as the etiologic agent of the fatal demyelinating disease, progressive multifocal leukoencephalopathy, which usually occurs in individuals with defects in cell-mediated immunity, including AIDS. However, upon mounting evidence of the oncogenic potential of the viral regulatory protein, T-antigen, and JCV's oncogenecity in a broad range of animal models, studies were initiated to determine its potential involvement in human carcinogenesis. Initially, the most frequently observed tumors in rodent models, including medulloblastoma, astrocytoma, glioblastoma, and other neural-origin tumors were analysed. These studies were followed by analysis of non-neural tumors such as colorectal carcinomas. In a subset of each tumor type examined, JC viral genomic DNA sequences could be detected by PCR and confirmed by Southern blot hybridization or direct sequencing. In a smaller subset of the tumors, the expression of T-antigen was observed by immunohistochemical analysis. Owing to the established functions of T-antigen including its ability to interact with tumor suppressor proteins such as Rb and p53, and its ability to influence chromosomal stability, potential mechanisms of JCV T-antigen-mediated cellular dysregulation are discussed. Further, as increasing evidence suggests that T-antigen is not required for maintenance of a transformed phenotype, a hit-and-run model for T-antigen-induced transformation is proposed.
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PMID:Human neurotropic polyomavirus, JCV, and its role in carcinogenesis. 1291 Feb 55

The nuclear receptors PPARs (peroxisome proliferator-activated receptors) are transcription factors activated by specific ligands. PPARs play an important role in carcinogenesis, inflammation, atherosclerosis, lipid metabolism and diabetes. There is evidence that activation of PPARs by specific ligands is able to suppress the growth of different types of human cancer by mechanisms including the growth arrest, apoptosis and induction of differentiation, although the detailed signalling pathways have not been completely elucidated to date. The aim of our study was to determine whether synthetic ligands of PPARalpha and PPARgamma could affect the viability, proliferation, differentiation, apoptosis and expression of some cell cycle related proteins in glial tumor cell lines. The study was performed on human glioblastoma cell lines U-87 MG, T98G, A172 and U-118 MG. Cell lines were treated by ligands of PPARalpha (bezafibrate, gemfibrozil) and PPARgamma (ciglitazone). MTT, flow cytometry, TUNEL assay and immunoblotting were used for detection of changes in cell viability, proliferation, differentiation and apoptosis. Bezafibrate, ciglitazone and gemfibrozil inhibited viability of glioblastoma cell lines. The synthetic ligands significantly reduced or induced the expression of cyclins, p27Kip1, p21Waf1/Cip1, MDM-2, Bcl-2, Bax, PARP, Caspase 3, androgen receptors, etc. and did not affect the expression of the differentiation marker GFAP. Flow cytometry confirmed arrest of the cell cycle although the detection of apoptosis was controversial. Apart from hypolipidemic and hypoglycaemic effects, PPAR ligands may also have significant cytostatic effects of potential use in anticancer treatment.
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PMID:Peroxisome proliferator-activated receptors (PPAR) agonists affect cell viability, apoptosis and expression of cell cycle related proteins in cell lines of glial brain tumors. 1580 Jul 11

Conjugated linoleic acid (CLA) has been shown to exert beneficial effects against carcinogenesis, atherosclerosis and diabetes. It has been demonstrated that CLA modulates lipid metabolism through the activation of peroxisome proliferator-activated receptors (PPARs). The PPAR family comprises 3 closely related gene products, PPAR alpha, beta/delta and gamma, differing for tissue distribution, developmental expression and ligand specificity. It has also been demonstrated that activated PPARgamma results in growth inhibition and differentiation of transformed cells. These observations stimulated a great interest toward PPARgamma ligands as potential anticancer drugs to be used in a differentiation therapy. Glioblastomas are the most commonly diagnosed primary tumors of the brain in humans. The prognosis of patients with high-grade gliomas is poor and only marginally improved by chemotherapy. The aim of this work was to study the effects of CLA and of a specific synthetic PPARgamma ligand on cell growth, differentiation and death of a human glioblastoma cell line as well as on parameters responsible for the metastatic behavior of this tumor. We demonstrate here that CLA and PPARgamma agonist strongly inhibit cell growth and proliferation rate and induce apoptosis. Moreover, both treatments decrease cell migration and invasiveness. The results obtained show that CLA acts, directly or indirectly, as a PPARgamma activator, strongly suggesting that this naturally occurring fatty acid may be used as brain antitumor drug and as a chemopreventive agent. Moreover, the gamma-agonist, once experimented and validated on man, may represent a useful coadjuvant in glioblastoma therapy and in the prevention of recurrences.
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PMID:PPARgamma-dependent effects of conjugated linoleic acid on the human glioblastoma cell line (ADF). 1598 37

Chemokines have been found to alter tumor growth and metastasis. We have described previously that a particular chemokine receptor, CXCR4, was predominantly expressed on various glioma cell lines and in resected glioblastoma specimens. Herein, we have tested the ligand of CXCR4, stromal cell derived factor-1alpha (SDF-1alpha, CXCL12), on the response of human glioma cells. We found that SDF-1alpha increased the expression of membrane type-2 matrix metalloproteinase (MT2-MMP), but not the other MT-MMPs, MMP-2 or MMP-9. The SDF-1alpha enhanced MT2-MMP expression was blocked by a CXCR4 antagonist, AMD3100. Functional invasion assays showed that SDF-1alpha stimulated glioma cells to invade through matrigel-coated chambers and this effect was inhibited in glioma cells by the stable downregulation of MT2-MMP expression using small interfering RNA (siRNA). In vivo and at asymptomatic stages following intracerebral implant of cells, mice harboring MT2-MMP siRNA downregulated clones had smaller and less invasive tumors compared with mice implanted with non-specific siRNA control cells. Analyses at symptomatic stages demonstrate that mice with MT2-MMP siRNA clones survive longer than mice harboring control cells. These results highlight MT2-MMP as an effector of CXCR4 signaling in glioma cells, and they reveal the novel role of MT2-MMP in modulating tumor activity.
Carcinogenesis 2005 Dec
PMID:The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase. 1603 74

Platelet-derived growth factor receptor (PDGFR) can bind to its ligand and consequently possess a kinase activity, and which is associated with the carcinogenesis of different cell types, including astrocytomas, oligodendrogliomas, and glioblastoma. In a cDNA microarray analysis, we observe the over-expressed mRNA of both PDGF-A and PDGF-alpha receptor in thyroid carcinoma cells. And the elevated protein expressions of PDGF-A and PDGF-alpha receptor in thyroid carcinoma cells were also confirmed by a Western blot analysis. The phosphorylation of PDGF-alpha receptor evaluated by an antibody against Tyr 720-phosphate was found in thyroid carcinoma cells. The tyrosine kinase activity of PDGF-alpha receptor was inhibited by tyrphostin AG1295 and showed a dose-dependent inhibition for the proliferation of thyroid carcinoma cells. These findings imply that autocrine activation of PDGF-alpha receptor plays a crucial role in the carcinogenesis of thyroid cells.
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PMID:An aberrant autocrine activation of the platelet-derived growth factor alpha-receptor in follicular and papillary thyroid carcinoma cell lines. 1612 35

SNAI1, SNAI2, and SNAI3 genes, encoding transcriptional repressors implicated in epithelial mesenchymal transition (EMT), are human homologs of Drosophila snail (sna) and slug genes. SNAI1 represses transcription of CDH1 (E-cadherin) gene. SNAI2 induces the first phase of EMT, including desmosome dissociation, cell spreading, and initiation of cell separation. Because SNAI family proteins are implicated in EMT during embryogenesis and carcinogenesis, SNAI family genes are potent targets of pharmacogenomics. Here, comparative genomics analyses and comparative proteomics analyses on SNAI family orthologs were performed. Rat Snai3 gene, consisting of three exons, was identified within rat genome sequence AC111791.4. Zebrafish snai1a (NM_131066.1) was identified as SNAI1 ortholog. Chicken ChEST362l17 (CR407272.1), Xenopus slug (AF368041.1), and zebrafish zgc92564 (NM_001008581.1) were identified as SNAI2 orthologs. Chicken snail (NM_ 205142.1), Xenopus snail (BC056857.1), and zebrafish snai1b (NM_130989.1) were identified as SNAI3 orthologs. SNAI1 orthologs consisted of SNAG domain and four zinc finger (ZNF) domains, while SNAI2 and SNAI3 orthologs consisted of SNAG domain and five ZNF domains. Based on the integromics analyses, SNAI2 orthologs were found to be more conserved than SNAI1 and SNAI3 orthologs. SNAI1 mRNA was expressed in placenta, neuroblastoma, and diffuse type gastric cancer. SNAI2 mRNA was expressed in placenta, melanocyte, embryonic stem (ES) cells, leiomyosarcoma, neuroblastoma, and glioblastoma. SNAI3 mRNA was expressed in B cells. Expression of SNAI3 mRNA was repressed due to the existence of anti-sense single-exon transcript. SNAI1, functioning as E-cadherin repressor, is implicated in the malignant infiltrating phenotype of diffuse type gastric cancer through the induction of EMT or fibroblastoid transformation.
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PMID:Comparative genomics on SNAI1, SNAI2, and SNAI3 orthologs. 1614 76


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