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)

We have characterized receptors for the insulin-like growth factor (IGF-I) on the mouse neuroblastoma cell line N18 as well as NG108, the hybrid cell line of N18 and rat glioma (C6). In this cell-free system, IGF-I and insulin stimulated the phosphorylation of 95-kDa and 105-kDa proteins. Using appropriate antibodies we were able to demonstrate that the IGF-I receptor beta subunit has two subtypes of 95 kDa and 105 kDa. On the other hand, insulin receptor beta subunit is a separate single 95-kDa protein. Enzymatic digestion of IGF-I receptor beta subunit subtypes by glycopeptidase F resulted in similar molecular masses (84 kDa and 86 kDa) on SDS-PAGE, which suggests that the difference in molecular masses between two subtypes is attributable to the differences in N-linked complex-type carbohydrate chains on the extracellular domain of beta subunits. This conclusion is further supported by peptides of similar molecular mass following staphylococcal V8 protease digestion. Analysis of IGF-I receptor beta subunit subtypes in these cells may provide insights into the mechanism of action of IGF-I on neural tissues.
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PMID:Insulin-like growth factor I receptors on mouse neuroblastoma cells. Two beta subunits are derived from differences in glycosylation. 296 5

To explore the antitumor effect of insulin-like growth factor 1 (IGF-I) antisense RNA and the interaction of IGF-I with insulin-like growth factor-binding proteins (IGFBPs) in glioma cells, a recombinant retrovirus expressing IGF-I antisense RNA was constructed and introduced into C6 glioma cells. IGF-I antisense RNA reverses the transformed phenotype in glioma cells and inhibits glioma cell growth by blocking overexpression of endogenous IGF-I. Expression of IGFBP-2 is increased in glioma cells as compared with normal adult glial cells. IGF-I antisense RNA also inhibits expression of IGFBP-2 in glioma cells, but does not influence expression of the other IGFBPs. Although IGFBP-2 in conditioned medium from wild-type C6 cell cultures itself does not directly influence glioma cell growth, it synergistically enhances exogenous IGF-I-mediated DNA synthesis in IGF-I-negative C6 cells. These findings indicate the inhibitory effect of IGF-I antisense RNA on growth and development of glioma cells. IGF-I-dependent glioma cell growth may, in some circumstances, require IGFBP-2 as a cofactor. The antitumor effect of IGF-I antisense RNA is also associated with inhibition of IGFBP-2 expression.
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PMID:Correlation of glioma cell regression with inhibition of insulin-like growth factor 1 and insulin-like growth factor-binding protein-2 expression. 938 Feb 78

To examine the relationship between the expression of insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) and cell growth in a cell type with a defined IGF/IGFBP system, an ovine IGFBP-2 complementary DNA was overexpressed in C6 glioma cells. C6 cells produce IGFBP-3, IGFBP-4, a negligible amount of IGFBP-2, and IGF-I. An ovine IGFBP-2 complementary DNA was transfected into C6 cells, and nine colonies that stably expressed variable levels of IGFBP-2 messenger RNA were selected. Synthesis of corresponding levels of IGFBP-2 was confirmed by ligand blot and immunoblot analyses of conditioned media. Three clones exhibited significantly reduced growth rates, and the remainder showed growth rates similar to those of the wild-type C6 cells. The clones, which overexpressed high levels of IGFBP-2 and IGF-I, had growth rates similar to the wild-type cells, whereas the three clones that overexpressed IGFBP-2 without a concomitant increase in IGF-I had reduced growth rates. In addition, a cell-associated IGFBP was identified in the slow growing clones, but not in the wild-type or the fast growing clones. This cell-associated IGFBP was deduced to be IGFBP-5 based on its molecular size, detection of IGFBP-5 messenger RNA only in slow growing clones, and competition of its binding by heparin. Growth of the slow growing clone, C6BP2-1, could not be overcome by the addition of exogenous IGF-I, suggesting that the cell-associated IGFBP-5 was the dominant regulator of IGF action. These observations suggested that 1) in C6 glioma cells cellular growth is altered by a disturbance in the equilibrium between IGF-I and IGFBPs and/or the functional properties of the IGFBPs; and 2) C6 cells may have a limited capacity to modulate IGF/IGFBP expression in response to changes in endogenous expression of IGFBPs. Endogenous regulation of the balance between IGFs and IGFBPs may be a model of regulation of cellular growth in tumor cells.
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PMID:Overexpression of insulin-like growth factor-binding protein-2 in C6 glioma cells results in conditional alteration of cellular growth. 992 80

The molecular mechanisms by which GH regulates insulin-like growth factor (IGF-I) gene expression remain obscure. One difficulty has been the lack of established GH-responsive cell lines that express the IGF-I gene. To develop such a cell line, we used rat C6 glioma cells which, as determined by RNase protection assay, express the IGF-I gene but not the GH receptor gene. To confer GH responsiveness, C6 cells were cotransfected with vectors that express the GH receptor (pRc/CMV WTrGHR) and Jak2 (pRc/CMV Jak2). GH responsiveness was demonstrated using luciferase reporter genes containing either the Sis-inducible element from the c-fos gene (pTK81-SIE-Luc) or 6 copies of the GH-responsive GAS-like element (GLE) from the rat spi2.1 gene (pSpi-GLE-Luc). The SIE is activated by binding of STAT1 and 3, whereas the GLE binds STAT5. In cells cotransfected with pRc/CMV WTrGHR, pRc/CMV Jak2, and either pTK81-SIE-Luc or pSpi GLE-Luc, treatment with 500 ng/ml GH for 24 h stimulated a 3.1- and 1.7-fold increase in luciferase activity, respectively. These data suggest that in C6 cells cotransfected with pRc/CMV WTrGHR and pRc/CMV Jak2, GH activates STAT1, 3, and 5. To determine whether GH-responsive IGF-I promoter activity could be demonstrated, C6 cells were cotransfected with pRc/CMV WTrGHR, pRc/ CMV Jak2, and an IGF-I-luciferase fusion gene that contained a fragment of the rat IGF-I gene that extended from -412 in the 5'-flanking region of exon 1 to the Met-22 in exon 3. GH stimulated a modest, but reproducible, 1.7-fold increase in luciferase activity in these cells, suggesting that a GH-responsive element is present in this region of the IGF-I gene. To better localize the GH-responsive element, cells were cotransfected with pRc/CMV WTrGHR, pRc/CMV Jak2 plus one of several IGF-I-luciferase fusion genes containing either fragments of one of the two promoters in the IGF-I gene or a fragment of intron 2 that includes a GH-responsive DNase I hypersensitivity site. For all constructs, treatment with GH for 24 h did not stimulate a significant increase in luciferase activity, suggesting that GH-responsive sequences are not located in these specific regions of the IGF-I gene or that GH-directed transcription of the IGF-I gene is mediated via several different regions of the IGF-I gene and the effect of any one of these regions in isolation was not sufficiently robust to be detected in this model system. In summary, transient expression of the GH receptor and Jak2 in C6 cells creates a GH-responsive system that activates STAT1, 3, and 5. Moreover, a fragment of the IGF-I gene that contains exons 1 and 2, a fragment of exon 3, and introns 1 and 2 is GH responsive using this model system.
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PMID:Growth hormone-mediated regulation of insulin-like growth factor I promoter activity in C6 glioma cells. 1038 99

The tumor suppressor gene PTEN (MMAC1, TEP1) encodes a dual-specificity phosphatase and is considered a progression-associated target of genetic alterations in human gliomas. Recently, it has been reported that the introduction of wild type PTEN into glioma cells containing endogenous mutant PTEN alleles (U87MG, LN-308), but not in those which retain wild-type PTEN (LN-18, LN-229), causes growth suppression and inhibits cellular migration, spreading and focal adhesion. Here, we show that PTEN gene transfer has no effect on the chemosensitivity of the four cell lines. Further, a correlational analysis of the endogenous PTEN status of 12 human glioma cell lines with their sensitivity to seven different cancer chemotherapy drugs reveals no link between PTEN and chemosensitivity. In contrast, ectopic expression of wild type PTEN, but not the PTEN(G129R) mutant, in PTEN-mutant gliomas markedly sensitizes these cells to irradiation and to CD95-ligand (CD95L)-induced apoptosis. PTEN-mediated facilitation of CD95L-induced apoptosis is associated with enhanced CD95L-evoked caspase 3 activity. Protein kinase B (PKB/Akt), previously shown to inhibit CD95L-induced apoptosis in nonglial COS7 cells, is inactivated by dephosphorylation. Interestingly, both PTEN-mutant U87MG and PTEN-wild-type LN-229 cells contain phosphorylated PKB constitutively. Wild-type PTEN gene transfer promotes dephosphorylation of PKB specifically in U87MG cells but not in LN-229 cells. Sensitization of U87MG cells to CD95L-apoptosis by wild-type PTEN is blocked by insulin-like growth factor-1 (IGF-1). The protection by IGF-1 is inhibited by the phosphoinositide 3-OH (PI 3) kinase inhibitor, wortmannin. Although PKB is a down-stream target of PI 3 kinase, the protection by IGF-1 was not associated with the reconstitution of PKB phosphorylation. Thus, PTEN may sensitize human malignant glioma cells to CD95L-induced apoptosis in a PI 3 kinase-dependent manner that may not require PKB phosphorylation.
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PMID:PTEN gene transfer in human malignant glioma: sensitization to irradiation and CD95L-induced apoptosis. 1043 16

Antagonists of growth hormone-releasing hormone(GH-RH)inhibit the growth of various cancers by mechanisms that involve the suppression of the insulin-like growth factor (IGF)-I and/or IGF-II. In view of the importance of the IGF system in glioma tumorigenesis, the effects of GH-RH antagonists MZ-5-156 and JV-1-36 were investigated in nude mice bearing subcutaneous and orthotopic xenografts of U-87MG human glioblastomas. After 4 weeks of therapy with MZ-5-156 or JV-1 -36 at the dose of 20 microg/day per animal, the final volume of subcutaneous U-87MG tumors was significantly (P < .01) decreased by 84% and 76%, respectively, as compared with controls. Treatment with GH-RH antagonists also reduced tumor weight and the levels of mRNA for IGF receptor type I (IGFR-I). A reduction in the mRNA levels for IGF-II was found in tumors of mice treated with MZ-5-156. Treatment with MZ-5-156 or JV-1 -36 also extended the survival of nude mice implanted orthotopically with U-87MG glioblastomas by 81% (P < .005) and 18%, respectively, as compared with the controls. Exposure in vitro to GH-RH antagonists MZ-5-156 or JV-1 -36 at 1 microM concentration for 24 hours decreased the tumorigenicity of U-87MG cells in nude mice by 10% to 30% and extended the latency period for the development of subcutaneous palpable tumors by 31% to 56%, as compared with the controls. Exposure of U-87MG cells to GH-RH antagonists in vitro also resulted in a time-dependent increase in the mRNA levels of IGFR-II or a decrease in the mRNA levels of IGFR-I. mRNA for GH-RH was detected in U-87MG cells and xenografts implying that GH-RH may play a role in the pathogenesis of this tumor. Our results suggest that GH-RH antagonists MZ-5-156 and JV-1-36 inhibit the growth of U-87MG human glioblastoma by mechanisms that involve the suppression of IGF system. Antagonistic analogs of GH-RH merit further development for the treatment of malignant glioblastoma.
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PMID:Antagonists of growth hormone-releasing hormone inhibit the growth of U-87MG human glioblastoma in nude mice. 1093 10

Human central nervous system tumors and glioma cell lines highly express the insulin-like growth factor-binding protein (IGFBP)-2. As IGFBP-2 can affect tumor growth, we studied the relationship between IGFBP-2 expression and the malignancy of brain tumors in vivo. To do so, we investigated by immunohistochemistry the accumulation of IGFBP-1, -2, and -3 in 50 human gliomas classified by the WHO Malignancy Scale. Double labeling using anti-CD68 (monocytes/macrophages), antiglial fibrillary acidic protein, and anti-CD3 (T cells) antibodies was performed to further characterize the IGFBP-1, -2, and -3(+) cells. The expression of IGFBP messenger RNAs (mRNAs) was tested by RT-PCR in tumor samples from nine gliomas of different grades and in eight cell lines representing the cellular composition of human glioma. As controls, the accumulation of IGFBP-2 was investigated in normal brain and in the rat C6 glioblastoma model. IGFBP-1 and -3 accumulated in endothelial and macrophage/microglial cells. IGFBP-2(+) macrophage/microglial and glioma cells clustered in the immediate vicinity of focal necrosis of the human gliomas as well as of the rat C6 glioblastoma. The labeling score of IGFBP-1 accumulation in endothelial cells correlated negatively (P: = 0.0229), and that of IGFBP-2 accumulation in glioma cells correlated positively (P: < 0.0006) with the tumor grade of the gliomas. In addition, RT-PCR analysis confirmed mRNA expression of IGFBP-1, -2, and -3 by the gliomas and glial cells. Small amounts of IGFBP-1 and -3 mRNA, but high amounts of IGFBP-2 mRNA, were detectable in macrophage-like and glioma cell lines. The results suggest cell type-specific accumulation of IGFBP-1, -2, and -3 in human glial tumors of the brain. The increase in IGFBP-2 expression with this malignancy suggests a role of IGFBP-2 in the biology of human gliomas.
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PMID:In vivo expression of insulin-like growth factor-binding protein-2 in human gliomas increases with the tumor grade. 1125 Sep 47

One goal for the gene expression profiling of cancer tissues is to identify signature genes that robustly distinguish different types or grades of tumors. Such signature genes would ideally provide a molecular basis for classification and also yield insight into the molecular events underlying different cancer phenotypes. This study applies a recently developed algorithm to identify not only single classifier genes but also gene sets (combinations) for use as glioma classifiers. Classifier genes identified by this algorithm are shown to be strong features by conservatively and collectively considering the misclassification errors of the feature sets. Applying this approach to a test set of 25 patients, we have identified the best single genes and two- to three-gene combinations for distinguishing four types of glioma: (a) oligodendroglioma; (b) anaplastic oligodendroglioma; (c) anaplastic astrocytoma; and (d) glioblastoma multiforme. Some of the identified genes, such as insulin-like growth factor-binding protein 2, have been confirmed to be associated with one of the tumor types. Using combinations of genes, the classification error rate can be significantly lowered. In many instances, neither of the individual genes of a two-gene set performs well as an accurate classifier, but the combination of the two genes forms a robust classifier with a small error rate. Two-gene and three-gene combinations thus provide robust classifiers possessing the potential to translate expression microarray results into diagnostic histopathological assays for clinical utilization.
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PMID:Identification of combination gene sets for glioma classification. 1247 4

Inhibition of epidermal growth factor receptor (EGFR) signaling sensitizes human malignant glioma cells to death ligand-induced apoptosis. However, tumor cells may compensate the loss of EGFR signaling by activation of the type 1 insulin-like growth factor receptor (IGF-1R). We here report that antagonism of the IGF-1R with the small-molecule inhibitor AG1024 in combination with inhibitors of the EGFR synergistically sensitizes human malignant glioma cells to CD95L-induced apoptosis. This cell death is p53-independent, but requires caspase 8 activity. The levels of the receptor, CD95, are not altered by the inhibitors alone or in combination. Analysis of the downstream signaling pathways reveals synergistic inhibition of ribosomal protein S6 phosphorylation by inhibitor co-treatment, suggesting an involvement of the mammalian target of rapamycin pathway. These findings suggest that adding inhibitors of IGF-1R may be a strategy to overcome escape from the anti-apoptotic effects of EGFR inhibition in malignant gliomas.
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PMID:Co-inhibition of epidermal growth factor receptor and type 1 insulin-like growth factor receptor synergistically sensitizes human malignant glioma cells to CD95L-induced apoptosis. 1535 39

In the study we report here, we tested the hypothesis that insulin-like growth factor-binding protein 2 (IGFBP2) promotes cell mobility through its interaction with integrin alpha5. Our previous microarray studies showed that IGFBP2 activates the expression of integrin alpha5. In addition, IGFBP2 has an Arg-Gly-Asp (RGD) domain, which is a known integrin binding motif. We first confirmed our microarray results by showing that the expression of integrin alpha5 is indeed up-regulated at the protein level in IGFBP2-overexpressing SNB19 glioma cells. Using co-immunoprecipitation, we confirmed that IGFBP2 does interact with integrin alpha5. To confirm that IGFBP2 interacts directly with integrin alpha5 through the RGD domain, we created an RGD --> RGE mutant (D306E) IGFBP2 and stably overexpressed the mutant IGFBP2 in the same cell line. Co-immunoprecipitation then showed that D306E-IGFBP2 had no detectable binding with integrin alpha5. We further observed that IGFBP2-overexpressing cells have extensive cell surface lamellipodia, whereas D306E-IGFBP2-overexpressing cells show abundant cell surface focal adhesions. Consistent with this, phenotype analysis then showed that IGFBP2-overexpressing cells have elevated migration rates compared with vector control; in contrast, the migration rates of the D306E-IGFBP2-overexpressing cells were not elevated and were comparable with that of vector control. Decreased expression of integrin alpha5 by small interference RNA in IGFBP2-overexpressing cells also reduced cell mobility. Therefore, we have concluded that one mechanism by which IGFBP2 activates IGFBP2-induced cell mobility is through its interaction with integrin alpha5 and this interaction is specifically mediated through the RGD domain on IGFBP2.
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PMID:An interaction between insulin-like growth factor-binding protein 2 (IGFBP2) and integrin alpha5 is essential for IGFBP2-induced cell mobility. 1656 42


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