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 monitored the volume of C6 glioma cells in suspension using a Coulter Counter and exposed the cells to micromolar or nanomolar levels of collagenase or clostripain. In 13 experiments, type IV collagenase (310 units ml-1; approximately 3 microM L-1) decreased the volume by 8-12%, 8 min after addition. In 13 of 21 experiments, the volume decrease was followed by a volume regulatory increase (VRI) back to control levels in the continued presence of collagenase. The shrinkage evoked by type IV collagenase was eliminated by heat-inactivation of the enzyme preparation. A highly purified collagenase (type VII) at the same concentration evoked a relatively minor decrease in volume. A well-known contaminating protease present in type IV collagenase, clostripain, which specifically cleaves arginyl peptide bonds, evoked a 7 +/- 2% shrinkage (100 nM L-1, 7 experiments). Clostripain did not evoke a volume regulatory increase. The initial velocity of shrinkage evoked by clostripain (0.0012 pL min-1, 0.0034 pL min-1, 0.0132 pL min-1; 1 pL = 10(-12) liters) scaled with its concentration (1 nM L-1, 10 nM L-1, 100 nM L-1). The effect of clostripain was inhibited by heat-inactivation of the enzyme. Leupeptin, an inhibitor of clostripain, prevented the decrease in volume evoked by clostripain. The activity of stretch-activated ion channels was unaffected by type IV collagenase. Barium, cesium, amiloride, DIDS, or bumetanide failed to block the shrinkage evoked by type IV collagenase. These results demonstrate that clostripain, present in crude collagenase enzyme preparations, causes the shrinkage, and that C6 glioma cells can undergo a volume regulatory increase at virtually constant osmotic pressure. In addition, cleavage of a cell surface moiety, which contains arginine, and possibly proline, causes shrinkage. This moiety may be part of the extracellular or intracellular matrix providing mechanical support to the cells. VRI reflect actions of another substance in the type IV crude collagenase preparations, on a receptor independent of the arg-pro moiety. The enzymatic modulation of glioma cell volume by these two receptors may reflect a new mechanism by which such cells, and possibly other glia, regulate their contact area and interactions with other cells in the central nervous system.
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PMID:Enzymatic modulation of cell volume in C6 glioma cells. 1040 29

Although the AP-1 transcription factor is known to play a role in cell proliferation and activation, it is also involved in apoptosis of cells in response to stress, DNA-damaging agents, or lack of survival signals. To understand how AP-1 might contribute to distinct biological processes, we tested a hypothesis that changes in AP-1 composition or phosphorylation state modulate its transcriptional activity during cyclosporin A-induced apoptosis of glioma cells. The induction of AP-1 DNA binding activity composed of c-Jun, JunB, JunD, and ATF-2 proteins preceded apoptosis. The compositional changes of AP-1 were associated with an elevation of c-Jun and JunB protein levels and the appearance of phosphorylated c-Jun and ATF-2 at 15-40 h posttreatment. Immunocytochemistry and staining with Hoechst 33258 revealed an accumulation of phosphorylated c-Jun protein in apoptotic cells. Because c-Jun expression and transcriptional activity are stimulated by phosphorylation at Ser63/73 by c-Jun N-terminal kinase (JNK), we measured JNK activities. We found prolonged induction of JNK activity in extracts from cyclosporin-treated cells, which suggests an involvement of persistent JNK activation in the initiation of glioma cell apoptosis. We provided evidence that variations in AP-1 composition and phosphorylation resulted in modification of trans-activating potential toward different promoters. Whereas collagenase AP-1/TRE-dependent transcription was down-regulated during apoptosis, Fas ligand promoter became activated.
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PMID:Changes of the trans-activating potential of AP-1 transcription factor during cyclosporin A-induced apoptosis of glioma cells are mediated by phosphorylation and alterations of AP-1 composition. 1061 4

In order to determine key MMPs for invasion and metastasis in various human cancers, we examined the expression of ten MMPs (MMP-1, 2, 3, 7, 8, 9, 13 and MT1, 2, 3-MMPs) and tissue inhibitors of metalloproteinases (TIMP-1 and 2) in breast carcinomas, thyroid papillary carcinomas, endometrial carcinomas, ovarian carcinomas, gastric adenocarcinomas, oral squamous cell carcinomas and gliomas. Of the MMPs examined, the activation of proMMP-2 by MT1-MMP (membrane type 1-MMP) was commonly important for the invasion and metastasis of these cancers except for endometrial carcinomas. The MMP-2 and MT1-MMP were localized to the carcinoma cells and gelatinolytic activity was demonstrated within the carcinoma cell nests by in situ zymography. In endometrial carcinomas, production and activation of proMMP-7 were a key determinant of the lymph node metastasis. The activation of proMMP-2 in gliomas involved MT2-MMP as well as MT1-MMP, and a combination of decreased TIMP-2 production and enhanced MT1-MMP expression was important in the subarachnoidal dissemination of glioblastoma cells. Brevican, a major adult brain proteoglycan, was degraded with MMP-1, 2, 3, 7, 10 and ADAMTS4 (aggrecanase-1) by being cleaved at the MMP site (the Ala360-Phe361 bond) with the MMPs and ADAM site (the Glu395-Ser396 bond) with ADAMTS4. Since activated MMP-2 and ADAMTS4 are present in human glioma tissues, they may play a key role in the invasion of glioma cells through the brevican degradation. The data in the present study suggest that the extracellular matrix-degrading metalloproteinases acting probably on the cell membranes of cancer cells are essential to the invasion and metastasis of human cancers.
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PMID:Tumor cell-matrix interaction: pericellular matrix degradation and metastasis. 1121 46

Degradation of basement membrane by metalloproteinases (MMP) is a critical step in tumor angiogenesis. To evaluate in vitro angiogenesis, several models have been employed, including bovine cornea, fenestrated rat brain, Matrigel, and others. These models did not provide quantitative analysis of capillary formation. The current study aimed for a novel approach to in vitro assay of angiogenesis with a "wet scanning electron microscope (SEM)" to investigate suppression of tumor angiogenesis by the MMP inhibitor, SI-27. The effects of noncytotoxic concentrations of SI-27 (1-100 microM) were determined on nonmitogenic vascular endothelial growth factor (VEGF) (10 ng/ml)-mediated cell motility and in vitro angiogenesis of human umbilical vein endothelial cells (HUVECs). Activities of MMP and tissue inhibitor of metalloproteinase (TIMP) were determined by enzyme-linked immunosorbent assay (ELISA). Subsequently, the inhibitory effect of SI-27 was examined on in vitro angiogenesis stimulated by supernatants of human glioma cell lines (U87MG, U251MG, or U373MG). In vitro angiogenesis was quantitatively analyzed with a variable-pressure SEM. Cell motility and in vitro angiogenesis by HUVECs were significantly increased by VEGF along with elevated MMP-1 and -2 activity, whereas SI-27 significantly suppressed VEGF-mediated in vitro angiogenesis and inactivated both MMP-1 and MMP-2, but not inhibited cell motility. The angiogenesis promoted by glioma supernatants showed a significant reduction in the presence of SI-27. SI-27, a novel MMP inhibitor, inhibited tumor angiogenesis in vitro. It can be anticipated to prevent tumor growth through its angiosuppressive effect. Quantitative analysis with a variable-pressure SEM is a novel approach to in vitro angiogenesis assay.
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PMID:Novel approach to analysis of in vitro tumor angiogenesis with a variable-pressure scanning electron microscope: suppression by matrix metalloproteinase inhibitor SI-27. 1190 79

Glioblastoma is a severe type of primary brain tumor and its invasion is strongly correlated with the secretion of matrix metalloproteinases (MMPs). To investigate a role of PTEN, a tumor suppressor gene, in the regulation of hyaluronic acid (HA)-induced invasion of glioma cells, we examined the secretion of MMP-9 in various glioma cells with or without a functional PTEN gene. The secretion of MMP-9 in glioma cells lacking functional PTEN (U87MG, U251MG, and U373MG) was induced by HA, although not in wildtype (wt)-PTEN-harboring cells (LN229, LN18, and LN428). In addition, stable expression of wt-PTEN into U87MG cells significantly decreased the secretion of HA-induced MMP-9 and basal levels of MMP-2, inhibiting the activation of focal adhesion kinase and extracellular signal-regulated kinase 1/2, whereas the secretion levels of the tissue inhibitor of metalloproteinase-1 and -2 were increased, finally resulting in the inhibition of invasion by HA in vitro. Ectopic expressions of adenoviral (Ad)-wt-PTEN and -lipid phosphatase-deficient (G129E)-PTEN, but not both protein and -lipid phosphatase-deficient (C124S)-PTEN, reduced MMP-9 secretion and invasion by HA. These results were also confirmed by expressions of Ad-wt-PTEN and Ad-G129E-PTEN in other glioblastoma cells lacking functional PTEN, U251MG, and U373MG. These findings strongly suggest the possibility that PTEN may block HA-induced MMP-9 secretion and invasion through its protein phosphatase activity.
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PMID:PTEN suppresses hyaluronic acid-induced matrix metalloproteinase-9 expression in U87MG glioblastoma cells through focal adhesion kinase dephosphorylation. 1241 63

Primary brain tumors (gliomas) have the unusual ability to diffusely infiltrate the normal brain thereby evading surgical treatment. Chlorotoxin is a scorpion toxin that specifically binds to the surface of glioma cells and impairs their ability to invade. Using a recombinant His-Cltx we isolated and identified the principal Cltx receptor on the surface of glioma cells as matrix metalloproteinase-2 (MMP-2). MMP-2 is specifically up-regulated in gliomas and related cancers, but is not normally expressed in brain. We demonstrate that Cltx specifically and selectively interacts with MMP-2 isoforms, but not with MMP-1, -3, and -9, which are also expressed in malignant glioma cells. Importantly, we show that the anti-invasive effect of Cltx on glioma cells can be explained by its interactions with MMP-2. Cltx exerts a dual effect on MMP-2: it inhibits the enzymatic activity of MMP-2 and causes a reduction in the surface expression of MMP-2. These findings suggest that Cltx is a specific MMP-2 inhibitor with significant therapeutic potential for gliomas and other diseases that invoke the activity of MMP-2.
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PMID:Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. 1245 20

A key feature in the malignant behavior of glioblastoma is the tendency to invade host brain tissue surrounding the primary tumor site. Several members of the matrix metalloproteinase family are thought to contribute to this invasive capacity. A single nucleotide polymorphism has been described in the matrix metalloproteinase-1 (MMP-1) promoter that consists of either the presence or absence of a guanine nucleotide at position -1607. The presence of the guanine base creates a functional binding site for members of the ETS family of transcription factors and has been shown to increase MMP-1 transcription. The purpose of our study was to characterize this polymorphism in human glioblastoma. Promoter genotyping was performed on brain tumor tissue obtained from 81 patients and compared to 57 healthy individuals. The 2G/2G genotype is more prevalent in glioblastoma tissue compared to healthy individuals (p = 0.01). mRNA and protein expression were measured in a subset of brain tumor and normal brain tissue samples. MMP-1 protein levels are significantly higher in glioblastoma tissue compared to normal brain (p = 0.001). Electromobility shift assays and promoter assays were performed to assess binding capability and transcriptional activity, respectively. Proteins present in glioma cell lines can specifically bind the 2G promoter probe. MMP-1 transcription is significantly higher in cells transfected with the 2G promoter when compared to cells transfected with the 1G promoter (p<0.02). This polymorphism may provide a mechanism for increased expression of MMP-1 in malignant gliomas via elevation of MMP-1 mRNA transcription and may underlie the invasive phenotype.
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PMID:Association of a single nucleotide polymorphism in the matrix metalloproteinase-1 promoter with glioblastoma. 1595 63

The abnormal expression of matrix metalloproteinases (MMPs) plays an important role in the invasion of malignant gliomas into the surrounding normal brain tissue. This study showed that curcumin has broad-spectrum inhibitory activity against MMP gene expression in human astroglioma cells. RNase protection assay showed that curcumin inhibited the PMA-induced mRNA expression of MMP-1, -3, -9, and -14. Curcumin repressed the DNA binding and transcriptional activities of AP-1, which is a common upstream modulator of MMP-1, -3, and -9 gene expression. In addition, curcumin suppressed the PMA-induced MAP kinase activities, which were differentially involved in modulating the MMPs. This suggests that the inhibition of MMP transcriptions by curcumin is mediated at least in part through the AP-1 and MAP kinase pathways. Curcumin was also found to significantly repress the in vitro invasion of glioma cells. Therefore, the broad-spectrum inhibition of MMP gene expression by curcumin might provide a novel therapeutic strategy for treating gliomas.
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PMID:Curcumin is a potent broad spectrum inhibitor of matrix metalloproteinase gene expression in human astroglioma cells. 1619 11

Matrix metalloproteinases (MMPs) play an important role in glioma infiltration, facilitating cell migration and tumor invasion through their ability to degrade the extracellular matrix. Therefore, the inhibition of MMPs has been suggested to be a promising therapeutic strategy for brain tumors. This study examined the effect of ginsenoside Rh2 on the expression of MMPs in human astroglioma cells. Rh2 inhibited the PMA-induced mRNA expression of MMP-1, -3, -9, and -14, suggesting that Rh2 has a broad-spectrum inhibitory effect on MMPs. The molecular mechanism underlying MMP-9 inhibition was further investigated because MMP-9 plays a major role in the invasiveness of glioma. It was found that Rh2 inhibited the secretion and protein expression of MMP-9 induced by PMA in human astroglioma cells. The Rh2-mediated inhibition of MMP-9 gene expression appears to occur through NF-kappaB and AP-1 because their DNA binding and transcriptional activities were suppressed by the agent. Furthermore, Rh2 significantly repressed the PMA-mediated activation of p38 MAPK, ERK and JNK, which are upstream modulators of NF-kappaB and AP-1. Finally, Rh2 inhibited the in vitro invasiveness of glioma cells, which might be attributed to the broad-spectrum inhibition of MMPs by Rh2. Overall, the strong inhibition of MMP expression by Rh2 might provide a potential therapeutic modality for brain tumors.
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PMID:Repression of matrix metalloproteinase gene expression by ginsenoside Rh2 in human astroglioma cells. 1788 Sep 28

Endoglin is a cell-surface adhesion protein as well as a coreceptor for transforming growth factor-beta (TGF-beta). It is located on endothelial and few other cells, but also found on certain tumor cells. Brain metastatic breast tumor cells derived from the MDA-MB-231 cell line heavily express endoglin in contrast to the corresponding parental ones. To clarify whether this determines their invasive phenotype, we compared their biological properties with endoglin-silenced brain-metastatic cells, low-expressing parental cells and these transfected with L- and S-endoglins, isoforms transducing or lacking TGF-beta signals. All L-endoglin-overexpressing cells were characterized by numerous invadopodia where endoglin was preferentially localized. Endoglin-expression resulted in elevated levels of the matrix metalloproteinases (MMP-1 and MMP-19) and downregulation of the plasminogen activator inhibitor-1. In Boyden-chamber and wound-healing assays, endoglin-overexpressing cells showed a considerably higher migration and chemotaxis to TGF-beta. In 3D spheroid confrontation assays between breast tumor cells and TGF-beta-secreting glioma cells, high L-endoglin-expressing cells invaded into the glioma-spheroids whereas low-endoglin-expressing cells dissociated in the culture; invasion was blocked by TGF-beta antibodies. In contrast to parental cells, endoglin-overexpressing cells invaded deeply into mouse brain slices. Thus, endoglin expression on tumor cells enhances their invasive character by formation of invadopodia, extracellular proteolysis, chemotaxis and migration.
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PMID:Endoglin expression in metastatic breast cancer cells enhances their invasive phenotype. 1822 85


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