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)

Aiming at identification of novel peptides that can be employed for effective targeting of malignant gliomas, we used a 12-mer peptide phage display library and cultured human malignant glioma cells for phage selection. Several common phage clones emerged after 4 rounds of biopanning against the U87MG glioblastoma cell line. The most abundant phage clone VTW, expressing a sequence of VTWTPQAWFQWV, bound to U87MG cells 700-fold more efficiently than the original unselected library. The VTW phage also bound strongly to other human glioma cell lines, including H4, SW1088 and SW1783, but very weakly to normal human astrocytes and SV40-immortalized human astroglial cells. When compared to other non-glial tumor cells, the phage showed 400- to 1400-fold higher binding efficiency for U87MG cells. After linked to positively charged lysine peptides, the VTW peptide became water soluble and was able to deliver biologically active, hydrophilic beta-galactosidase into U87MG cells, with up to 90% of the cells being stained intensively blue. This peptide carrier did not show obvious protein delivery activities in the human astrocytes. Our results provide a proof of principle to the concept that peptides identified through phage display technology can be used to develop protein carriers that are capable of mediating intracellular delivery of hydrophilic macromolecules in a tumor cell-specific manner.
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PMID:A peptide-based carrier for intracellular delivery of proteins into malignant glial cells in vitro. 1863 77

Sodium-dependent glutamate uptake is essential for limiting excitotoxicity, and dysregulation of this process has been implicated in a wide array of neurological disorders. The majority of forebrain glutamate uptake is mediated by the astroglial glutamate transporter, GLT-1. We and others have shown that this transporter undergoes endocytosis and degradation in response to activation of protein kinase C (PKC), however, the mechanisms involved remain unclear. In the current study, transfected C6 glioma cells or primary cortical cultures were used to show that PKC activation results in incorporation of ubiquitin into GLT-1 immunoprecipitates. Mutation of all 11 lysine residues in the amino and carboxyl-terminal domains to arginine (11R) abolished this signal. Selective mutation of the seven lysine residues in the carboxyl terminus (C7K-R) did not eliminate ubiquitination, but it completely blocked PKC-dependent internalization and degradation. Two families of variants of GLT-1 were prepared with various lysine residues mutated to arginine. Analyses of these constructs indicated that redundant lysine residues in the carboxyl terminus were sufficient for the appearance of ubiquitinated product and degradation of GLT-1. Together these data define a novel mechanism by which the predominant forebrain glutamate transporter can be rapidly targeted for degradation.
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PMID:Ubiquitination-mediated internalization and degradation of the astroglial glutamate transporter, GLT-1. 1880 48

Temozolomide (TMZ) and carmustine (BCNU), cancer-drugs usually used in the treatment of gliomas, are DNA-methylating agents producing O6-methylguanine. It has been shown that 06-methylguanine triggers DNA mismatch repair and in turn induce apoptosis and senescence, respectively, over a 4 and 6 days period [Y. Hirose, M.S. Berger, R.O. Pieper, p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells, Cancer Res. 61 (2001) 1957-1963; W. Roos, M. Baumgartner, B. Kaina, Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1, Oncogene 23 (2004) 359-367]. Here we show that TMZ and BCNU have an earlier effect on nuclear organization and chromatin structure. In particular, we report that TMZ and BCNU induce clustering of pericentromeric heterochromatin regions and increase the amount of heterochromatic proteins MeCP2 and HP1alpha bound to chromatin. These drugs also decrease global levels of histone H3 acetylation and increase levels of histone H3 trimethylated on lysine 9 (H3-triMeK9). These events precede the senescence status. We conclude that TMZ and BCNU efficacy in glioma treatment may implicate a first event characterized by changes in heterochromatin organization and its silencing which is then followed by apoptosis and senescence.
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PMID:Temozolomide and carmustine cause large-scale heterochromatin reorganization in glioma cells. 1911 35

In an attempt to develop effective vaccines against central nervous system (CNS) tumors, we evaluated the ability of vaccines with standard dendritic cells (DC) versus type 1 polarizing DCs (DC1) to induce glioma-specific type 1 CTLs with CNS tumor-relevant homing properties and the mechanism of their action. C57BL/6 mouse-derived bone marrow cells were cultured with mouse granulocyte/macrophage colony-stimulating factor (GM-CSF) for 6 days, and CD11c(+) cells were subsequently cultured with GM-CSF, rmIFN-gamma, rmIFN-alpha, rmIL-4, and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for 24 hours to generate DC1s. In analogy to their human counterparts, mouse DC1s exhibited surface marker profiles of mature DCs and produced high levels of IL-12 and CXCL10. Importantly for their application as cancer vaccines, such DC1s stably retained their type 1 phenotype even when exposed to type 2-promoting or regulatory T cell (Treg)-promoting environments. Consistently, mouse DC1s induced antigen-specific type 1 CTLs more efficiently than nonpolarized DCs in vitro. DC1s given s.c. migrated into draining lymph nodes, induced antigen-specific CTLs, and suppressed Treg accumulation. In addition, s.c. immunization with DC1s loaded with glioma-associated antigen (GAA)-derived CTL epitope peptides prolonged the survival of CNS GL261 glioma-bearing mice, which was associated with efficient CNS glioma homing of antigen-specific CTLs. Intratumoral injections of GAA peptide-loaded DC1s further enhanced the anti-CNS glioma effects of DC1-based s.c. immunization. Interestingly, the antitumor functions were abrogated with CXCL10(-/-) mouse-derived DC1s. Collectively, these findings show the anti-CNS glioma effects of DC1-based therapy and a novel role of CXCL10 in the immunologic and therapeutic activity of DC-based cancer vaccines.
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PMID:Effective immunotherapy against murine gliomas using type 1 polarizing dendritic cells--significant roles of CXCL10. 1919 Mar 35

The MMAC/PTEN tumor suppressor gene has an essential biological role in the formation of glioblastomas. It is known that there are variations in genetic alterations in tumors that develop in patients with different ethnic backgrounds; thus, we aimed to evaluate the incidence of MMAC/PTEN mutations and protein expression among various low grade gliomas of Turkish patients. We investigated 28 low grade gliomas for mutations of the MMAC/PTEN gene using single strand conformational polymorphism method followed by DNA sequencing. Additionally, the level of MMAC/PTEN protein expression in the tissues of 26 tumors was assessed by immunohistochemistry. In our investigation, MMAC/PTEN mutations were detected in 2 of 28 tumors (7.14%). One novel sequence variant G --> A transition at codon 159 was identified. This missense variation was a result of an alteration from AGG (Arginine) to AAG (Lysine). Moreover, it was observed that MMAC/PTEN protein expression was reduced to 73.08% of tumors. In conclusion, reduced MMAC/PTEN expression by genetic and/or epigenetic mechanisms in low grade gliomas might be associated with glioma tumorigenesis.
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PMID:Investigation of MMAC/PTEN gene mutations and protein expression in low grade gliomas. 1935 Mar 82

Although the safety of vaccine approaches for central nervous system (CNS) malignancies has been established in early phase clinical trials, the success of a vaccine strategy will depend critically on the ability of effector T cells to home in to CNS tumors and durably exert antitumor effects. Based on our recent studies, efficient CNS tumor homing is a characteristic of cytotoxic T lymphocytes (CTLs) with a type 1 phenotype (Tc1), and this appears to be related to the Tc1 response to the type 1 CXC chemokine ligand (CXCL) 10 [also known as interferon (IFN)-inducible protein (IP)-10] and expression of an integrin receptor very late antigen (VLA)-4 on Tc1. In addition, we have previously shown that direct intratumoral delivery of dendritic cells (DCs) ex vivo engineered to secrete IFN-alpha further enhances Tc1 homing via upregulation of CXCL10/IP-10 in the tumor microenvironment. As a means to induce IFN-alpha and CXCL10/IP-10 in the CNS tumor microenvironment in a clinically feasible manner, we used administration of polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose (poly-ICLC), a ligand for toll-like receptor 3 and melanoma differentiation-associated gene 5 (MDA5) in combination with vaccinations targeting CTL epitopes derived from glioma-associated antigens (GAAs). The combination of subcutaneous vaccination and i.m. poly-ICLC administration remarkably promoted systemic induction of antigen GAA-specific Tc1s expressing VLA-4 in the CNS tumors and improved the survival of tumor-bearing mice in the absence of detectable autoimmunity. Based on these data, we have implemented a phase I/II vaccination study using type 1 polarizing DCs loaded with GAA peptides in combination with poly-ICLC in patients with recurrent malignant glioma.
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PMID:Brain tumor immunotherapy with type-1 polarizing strategies. 1976 32

Sotos syndrome is an autosomal dominant condition characterized by overgrowth resulting in tall stature and macrocephaly, together with an increased risk of tumorigenesis. The disease is caused by loss-of-function mutations and deletions of the nuclear receptor SET domain containing protein-1 (NSD1) gene, which encodes a histone methyltransferase involved in chromatin regulation. However, despite its causal role in Sotos syndrome and the typical accelerated growth of these patients, little is known about the putative contribution of NSD1 to human sporadic malignancies. Here, we report that NSD1 function is abrogated in human neuroblastoma and glioma cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also demonstrate that the epigenetic inactivation of NSD1 in transformed cells leads to the specifically diminished methylation of the histone lysine residues H4-K20 and H3-K36. The described phenotype is also observed in Sotos syndrome patients with NSD1 genetic disruption. Expression microarray data from NSD1-depleted cells, followed by ChIP analysis, revealed that the oncogene MEIS1 is one of the main NSD1 targets in neuroblastoma. Furthermore, we show that the restoration of NSD1 expression induces tumor suppressor-like features, such as reduced colony formation density and inhibition of cellular growth. Screening a large collection of different tumor types revealed that NSD1 CpG island hypermethylation was a common event in neuroblastomas and gliomas. Most importantly, NSD1 hypermethylation was a predictor of poor outcome in high-risk neuroblastoma. These findings highlight the importance of NSD1 epigenetic inactivation in neuroblastoma and glioma that leads to a disrupted histone methylation landscape and might have a translational value as a prognostic marker.
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PMID:Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma. 2001 18

Epigenetic parameters (DNA methylation, histone modifications, and miRNAs) play a significant role in cancer. To identify the common epigenetic signatures of both the individual matrix metalloproteinases (MMPs) and the additional genes, the function of which is also linked to proteolysis, migration, and tumorigenesis, we performed epigenetic profiling of 486 selected genes in unrelated non-migratory MCF-7 breast carcinoma and highly migratory U251 glioma cells. Genome-wide transcriptional profiling, quantitative reverse transcription-PCR, and microRNA analyses were used to support the results of our epigenetic studies. Transcriptional silencing in both glioma and breast carcinoma cells predominantly involved the repressive histone H3 Lys-27 trimethylation (H3K27me3) mark. In turn, epigenetic stimulation was primarily performed through a gain in the histone H3 Lys-4 dimethylation (H3K4me2) and H3 hyperacetylation and by a global reduction of H3K27me3. Inactive pro-invasive genes in MCF-7 cells but not in U251 cells frequently exhibited a stem cell-like bivalent mark (enrichment in both H3K27me3 and H3K4me2), a characteristic of developmental genes. In contrast with other MMPs, MMP-8 was epigenetically silenced in both cell types, thus providing evidence for the strict epigenetic control of this anti-tumorigenic proteinase in cancer. Epigenetic stimulation of multiple collagen genes observed in cultured glioma cells was then directly confirmed using orthotopic xenografts and tumor specimens. We suggest that the epigenetic mechanisms allow gliomas to deposit an invasion-promoting collagen-enriched matrix and then to use this matrix to accomplish their rapid migration through the brain tissue.
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PMID:Microarray-based transcriptional and epigenetic profiling of matrix metalloproteinases, collagens, and related genes in cancer. 2040 28

Stimulation of double-stranded (ds)RNA receptors can increase the effectiveness of cancer vaccines, but the underlying mechanisms are not completely elucidated. In this study, we sought to determine critical roles of host IFN-alpha and IFN-gamma pathways in the enhanced therapeutic efficacy mediated by peptide vaccines and polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in the murine central nervous system (CNS) GL261 glioma. C57BL/6-background wild type (WT), IFN-alpha receptor-1 (IFN-alphaR1)(-/-) or IFN-gamma(-/-) mice bearing syngeneic CNS GL261 glioma received subcutaneous (s.c.) vaccinations with synthetic peptides encoding CTL epitopes with or without intramuscular (i.m.) injections of poly-ICLC. The combinational treatment induced a robust transcription of CXCL10 in the glioma site. Blockade of CXCL10 with a specific monoclonal antibody (mAb) abrogated the efficient CNS homing of antigen-specific type-1 CTL (Tc1). Both IFN-alphaR(-/-) and IFN-gamma(-/-) hosts failed to up-regulate the CXCL10 mRNA and recruit Tc1 cells to the tumor site, indicating non-redundant roles of type-1 and type-2 IFNs in the effects of poly-ICLC-assisted vaccines. The efficient trafficking of Tc1 also required Tc1-derived IFN-gamma. Our data point to critical roles of the host-IFN-alpha and IFN-gamma pathways in the modulation of CNS glioma microenvironment, and the therapeutic effectiveness of poly-ICLC-assisted glioma vaccines.
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PMID:Poly-ICLC promotes the infiltration of effector T cells into intracranial gliomas via induction of CXCL10 in IFN-alpha and IFN-gamma dependent manners. 2054 6

Acid-sensing ion channel 1 (ASIC1) is a H(+)-gated channel of the amiloride-sensitive epithelial Na(+) channel (ENaC)/degenerin family. ASIC1 is expressed mostly in the central and peripheral nervous system neurons. ENaC and ASIC function is regulated by several serine proteases. The type II transmembrane serine protease matriptase activates the prototypical alphabetagammaENaC channel, but we found that matriptase is expressed in glioma cells and its expression is higher in glioma compared with normal astrocytes. Therefore, the goal of this study was to test the hypothesis that matriptase regulates ASIC1 function. Matriptase decreased the acid-activated ASIC1 current as measured by two-electrode voltage clamp in Xenopus oocytes and cleaved ASIC1 expressed in oocytes or CHO K1 cells. Inactive S805A matriptase had no effect on either the current or the cleavage of ASIC1. The effect of matriptase on ASIC1 was specific, because it did not affect the function of ASIC2 and no matriptase-specific ASIC2 fragments were detected in oocytes or in CHO cells. Three matriptase recognition sites were identified in ASIC1 (Arg-145, Lys-185, and Lys-384). Site-directed mutagenesis of these sites prevented matriptase cleavage of ASIC1. Our results show that matriptase is expressed in glioma cells and that matriptase specifically cleaves ASIC1 in heterologous expression systems.
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PMID:Proteolytic cleavage of human acid-sensing ion channel 1 by the serine protease matriptase. 2060 29


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