Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anti-proliferative activity of human interferon (HuIFN) was enhanced by dipyridamole, 2,6-bis-(diethanolamino)-4,8-dipiperidinopyrimido-[5,4-d]-py rimidine, when tested against various human tumor cell lines, including KT (breast carcinoma), PLC/PRF/5 (hepatoma), MGC-I, U251-SP and T98 (glioma), HAC-2 and SHIN-3 (ovarian carcinoma), and MM-ICB (melanoma). The enhancement occurred irrespective of the kind of HuIFN used (alpha, beta or gamma) and the original degree of susceptibility of the cells to HuIFN. Even low doses down to 0.01 microM of dipyridamole that had no intrinsic anti-proliferative activity could enhance the effect of HuIFN. The enhancement of HuIFN effects seems not to be caused by induction of HuIFN production, because neither anti-viral activity nor HuIFN antigens were detected in culture medium in cells treated with dipyridamole. Mopidamole, a derivative of dipyridamole lacking one piperidine residue, produced little enhancement of the effects of HuIFN. Among ovarian cancer cell lines tested, the enhancement of the activity of HuIFN by dipyridamole for HAC-2 and SHIN-3 cells was equivalent to or greater than that for 3 chemotherapy agents (adriamycin, vincristine, and a camptothecin derivative). However, neither HOC-21 ovarian cancer cells nor HEC-1 endometrial adenocarcinoma cells were susceptible to any combinations. When MGC-1, U251-SP, and HAC-2 cells were injected into nude mice, the growth of tumors was more markedly inhibited by the subcutaneous administration of HuIFN in combination with oral administration of dipyridamole than by the HuIFN alone. Thus, this combination therapy seems to be worth trying for human cancer, although the enhancement of the effects of HuIFN by dipyridamole varied among the cell lines examined.
 ...
PMID:Dipyridamole enhances an anti-proliferative effect of interferon in various types of human tumor cells. 137 1

In the neuroblastoma X glioma hybrid cell line NG108-15, bradykinin (BK) receptor stimulation induced a rapid and concentration-dependent rise in cytosolic free Ca2+ levels, as measured with the Ca2(+)-sensitive fluorescent dye fura-2. The Ca2+ transient was present in the absence of extracellular Ca2+ and was associated with a concentration-dependent production of inositol phosphates, particularly inositol trisphosphate (InsP3). Pretreatment of intact NG108-15 cells with forskolin or dibutyryl-cAMP plus isobutylmethylxanthine reduced BK-stimulated InsP3 production and the increase in cytosolic free Ca2+. Membranes prepared from forskolin- and [3H]inositol-pretreated NG108-15 cells also showed a diminished production of InsP3 elicited by guanosine 5'-[gamma-thio]triphosphate, NaF, or BK plus GTP. On the other hand, the Ca2+ sensitivity of membrane-associated phosphoinositide-specific phospholipase C (PI-PLC) was unaffected by forskolin pretreatment of intact NG108-15 cells. Collectively, these results suggest that A-kinase may inhibit receptor-mediated and postreceptor stimulation of PI-PLC in neuron-like cells, perhaps by impairing the coupling between a guanine nucleotide-binding protein and PI-PLC.
 ...
PMID:Cyclic AMP inhibits inositol polyphosphate production and calcium mobilization in neuroblastoma X glioma NG108-15 cells. 216 7

Phospholipase C-beta 1 (PLC-beta 1) exists as two immunologically indistinguishable polypeptides of 150 and 140 kDa and is encoded in rat brain by two distinct transcripts of 5.4 and 7.2 kilobases (kb). cDNA corresponding to the entire 5.4-kb transcript as reported previously reveals an open reading frame that is capable of coding a 1216-amino acid polypeptide (Suh, P. G., Ryu, S. H., Moon, K. H., Suh, H. W., and Rhee, S. G. (1988) Cell 54, 161-169). We have now isolated cDNAs corresponding to the entire 7.2-kb transcript from a rat brain cDNA library. The 7.2-kb transcript differs from the previously reported 5.4-kb transcript by possessing both an additional 118 nucleotides located near the end of the coding sequence and a 1738-nucleotide extension of the 3'-flanking region. The presence of the 118-nucleotide insert in the cumulative 7.2-kb sequence gives rise to an open reading frame that is capable of coding a 1173-amino acid polypeptide (PLC-beta 1b), the carboxyl-terminal sequence of which differs from that of the 1216-amino acid polypeptide (PLC-beta 1a) derived from the 5.4-kb transcript. Antibodies were raised against synthetic peptides corresponding to the carboxyl-terminal portions of PLC-beta 1a and PLC-beta 1b. Immunoblot analysis with these isozyme-specific antibodies revealed that both PLC-beta 1a and PLC-beta 1b are expressed in rat brain and C6Bu-1 glioma cells and that PLC-beta 1a and PLC-beta 1b correspond to the previously identified 150- and 140-kDa PLC-beta 1 enzymes, respectively. Analysis of PLC-beta 1 genomic DNA indicates that PLC-beta 1a and PLC-beta 1b are derived from a single gene by alternative RNA splicing.
 ...
PMID:Two forms of phospholipase C-beta 1 generated by alternative splicing. 751 Jun 82

Phosphatidylinositol(PI)-specific phospholipase C activity was detected on the surface of rat astrocytes, rat C6 glioma cells, and rat embryo (REF52) fibroblasts. The cell surface phospholipase C (ecto-PLC) activity was calcium-dependent, did not result from secreted phospholipase C, and was not released from the cell surface by bacterial PI-specific phospholipase C. Agents known to stimulate intracellular PI turnover, including carbachol, L-glutamic acid, acetylcholine, and orthovanadate, did not induce measurable alterations in the activity of the ecto-PLC. The expression of ecto-PLC activity by REF52 fibroblasts was density-dependent: subconfluent cultures of REF52 exhibited low levels of activity (less than 80 pmol of inositol phosphate formed/min/10(6) cells), whereas in confluent cultures ecto-PLC activity increased to approximately 300 pmol/min/10(6) cells. In contrast to this behavior and that exhibited by previously reported ecto-PLC-positive cell types, the ecto-PLC activity exhibited by astrocytes (approximately 1,000 pmol/min/10(6) cells) and by C6 glioma cells (approximately 100 pmol/min/10(6) cells) was independent of cell culture density up to confluence. The constitutive expression of ecto-PLC activity of astroglial cells may be related to their function as accessory cells in close association with neurons.
 ...
PMID:Differential expression of phospholipase C specific for inositol phospholipids at the cell surface of rat glial cells and REF52 rat embryo fibroblasts. 838 Apr 38

Malignant human gliomas are the most common forms of primary tumors in the central nerve system. Due to their location and invasive nature, treatment so far has been mainly palliative. Thus, understanding the molecular detail of tumor transformation and progression is crucial for developing effective therapeutic strategy for this fetal tumor. Among the genetic alternations found in these tumors, p53 inactivation and PDGF/PDGFR activation represent the early events, and the loss of chromosome 10 and gene amplification and rearrangement of EGFR represent the late events. Studies with both glioma cell lines and primary tumor tissues have strongly suggested that TGF-alpha and EGFR function as an important autocrine loop in supporting proliferation of human glioma, especially in high grade glioma, since elevated TGF-alpha expression is also found in these high grade tumors. Furthermore, down regulation of the expression of TGF-alpha by antisense constructs has been shown to inhibit several types of human tumor cell growth including glioma. Other means of therapeutic approaches using this autocrine loop as a target also include the use of monoclonal antibodies and their cytotoxic conjugated. Considerable understanding of the EGFR-mediated signal transduction pathways has become available recently, which including GRB2/mSOS1 mediated MAP kinase activation; JAK/STATs pathway; PLC-gamma pathway. However, much work still needs to be done before a specific component of these pathways can be applied for effective control of tumor growth in the clinic.
 ...
PMID:The autocrine loop of TGF-alpha/EGFR and brain tumors. 944 27

Phospholipase C-beta1 (PLC-beta1), one of the PLC-beta isozymes, exists as two immunologically distinguishable polypeptides of 150 (PLC-beta1a) and 140 kDa (PLC-beta1b) which are encoded in two distinct transcripts and generated by alternative splicing of a single gene. In this study, the subcellular localization of the two phospholipases C-beta1 proteins was examined in rat C6Bu-1 glioma cells using immunological techniques. Immunoblot analysis revealed that the two forms of PLC-beta1 were detectable in both cytosolic and nuclear fractions. PLC-beta1a appeared to be located preferentially in the cytosol, whereas PLC-beta1b was found predominantly in the nuclei of C6Bu-1 cells. Immunocytochemical experiments confirmed the differential localization of the two PLC-beta1 species in C6Bu-1 cells. These results suggest that the two PLC-beta1 proteins may have different physiological roles in the cell.
 ...
PMID:Localization of two forms of phospholipase C-beta1, a and b, in C6Bu-1 cells. 944 6

Activation of the delta-opioid receptor in NG108-15 neuroblastoma X glioma hybrid cells results in a transient increase at the intracellular level of inositol-1,4,5-triphosphate [Ins(1,4,5)P3]. This time course in the transient increase in the Ins(1,4,5)P3 level is distinctly different from that observed in the homologous opioid receptor desensitization as measured by the inhibition of adenylyl cyclase activity. One probable mechanism for this rapid loss in Ins(1,4,5)P3 response is the feedback regulation of the phospholipase C activity. Regulation by protein phosphorylation was suggested by the observations that the opioid-mediated response was potentiated by calphostin C, an inhibitor of protein kinase C (PKC), and was abolished by either phorbol-12-myristate-13-acetate, a PKC activator, or calyculin A, a protein phosphatase1/2A inhibitor. The direct phosphorylation of phospholipase C was demonstrated by immunoprecipitation of PLC-beta3 from metabolically labeled NG108-15 cells challenged with the delta-selective agonist [D-Pen2, D-Pen5]enkephalin (DPDPE). A time- and DPDPE concentration-dependent and naloxone-reversible increase in the PLC-beta3 phosphorylation can be demonstrated. This PLC-beta3 phosphorylation was mainly due to PKC activation because pretreatment of NG108-15 cells with calphostin C could block the DPDPE effect. Activation of the PLC-beta3 by DPDPE was one of the prerequisites for agonist-mediated PLC-beta3 phosphorylation because the aminosteroid phospholipase C inhibitor U73122 could block the DPDPE effect. In addition to DPDPE, lysophosphatidic acid (LPA) stimulated the PLC-beta3 phosphorylation, but bradykinin did not. Furthermore, the LPA- and DPDPE-mediated PLC-beta3 phosphorylation was additive and was much less than that observed with phorbol-12-myristate-13-acetate. The effect of DPDPE was specific to PLC-beta3; the betagamma-insensitive phospholipase C-beta1 was not phosphorylated in the presence of either DPDPE or LPA. These results indicate that although PKC phosphorylation of PLC-beta3 is not obligatory for the opioid receptor desensitization, it seems to play a significant facilatory role in the mechanisms allowing desensitization of opioid-activated phospholipase C response before that of adenylyl cyclase inhibition.
 ...
PMID:Contribution of phospholipase C-beta3 phosphorylation to the rapid attenuation of opioid-activated phosphoinositide response. 961 7

We have previously shown that, in glioma C6 cells, two nucleotide ADP-sensitive receptors coexist: P2Y1, coupled to PLC and responsible for Ca2+ release, and P2Y12, negatively coupled to adenylate cyclase. In the present study, we examined the effects of the stimulation of these two receptors on ERK1/2 and PI3-K activation, and cell proliferation in either serum-deprived or nonstarved C6 cells. In response to ADP and its analogues, in serum-starved cells, both p44 ERK1 and p42 ERK2 were activated in a time-dependent manner, as monitored by Western blot analysis using an antiphospho-p42/p44 MAPK antibody. The phosphorylation was reduced both by removal of the extracellular Ca2+ and partially or almost completely by MRS2179 or AR-C69931MX, specific antagonists of the P2Y1 and P2Y12 receptors, respectively. The inhibitory effect of antagonists was additive. These data indicate the involvement of both receptors, P2Y1 and P2Y12, in the ERK1/2 activation, but the P2Y12 receptor contribution predominates. ERK1/2 activity was positively correlated with cell proliferation of cultured glioma C6 cells. In nonstarved cells, ADP markedly decreased the PI3-K activity. In contrast, in serum-starved cells, ADP evoked an increase in the PI3-K activity. Blocking of the P2Y1 receptor by MRS2179 additionally increased this ADP response. These results suggest that the P2Y1 receptor has an inhibitory and the P2Y12 receptor a stimulatory effect on PI3-K signalling pathway. RT-PCR analysis revealed different mRNA expression of both receptors in starved and nonstarved cells. In nonstarved cells, the P2Y1 receptor mRNA predominates, whereas in serum-deprived cells the expression of P2Y12 mRNA becomes more pronounced. British Journal of Pharmacology (2004) 141, 497-507. doi:10.1038/sj.bjp.0705639
 ...
PMID:Differential effects of P2Y1 and P2Y12 nucleotide receptors on ERK1/ERK2 and phosphatidylinositol 3-kinase signalling and cell proliferation in serum-deprived and nonstarved glioma C6 cells. 1471 52

Valproic acid (VPA), which has demonstrated efficacy in the treatment of bipolar disorder, has been shown to alter components of the phosphoinositide (PI) signaling cascade and to increase gene expression mediated by the transcription factor activator protein 1 (AP-1). Central serotonin-2A (5-HT2A) receptors, which have been implicated in the pathophysiology of manic-depressive illness, are coupled to PI hydrolysis. The promoter region of the 5-HT2A receptor gene contains AP-1 binding sites. We examined in C6 glioma cells the effect of VPA on 5-HT2A receptor signaling. Treatment of cells with VPA (100 microg/mL) for 20 h, but not 1.5 h, resulted in an enhancement of 5-HT2A receptor-stimulated PI hydrolysis. This effect of 20-h VPA exposure appeared not to be at the level of G protein or effector (i.e. phospholipase C: PLC) as inositol phosphate accumulation stimulated by aluminum fluoride or the PLC activator 2,4,6-trimethyl-N-(m-3-trifluromethylphenyl) benzenesulfonamide was not increased. The number of 5-HT2A receptors, as determined in saturation binding experiments using [3H]ketanserin, was increased by 20-h VPA treatment, with no change in affinity (KD). Taken together, our data suggest that the increase in 5-HT2A receptor-mediated PI hydrolysis following 20-h VPA exposure is not due to a general effect of VPA on this signaling cascade, but due to the up-regulation of 5-HT2A receptor number.
 ...
PMID:Effect of valproic acid on serotonin-2A receptor signaling in C6 glioma cells. 1531 82

Signal transduction from plasma membrane to cell nucleus is a complex process depending on various components including lipid signaling molecules, in particular phosphoinositides and their related enzymes, which act at cell periphery and/or plasma membrane as well as at nuclear level. As far as the nervous system may concern the inositol lipid cycle has been hypothesized to be involved in numerous neural as well as glial functions. In this context, however, a precise panel of glial PLC isoforms has not been determined yet. In the present experiments we investigated astrocytic PLC isoforms in astrocytes obtained from foetal primary cultures of rat brain and from an established cultured (C6) rat astrocytoma cell line, two well known cell models for experimental studies on glia. Identification of PLC isoforms was achieved by using a combination of RT-PCR and immunocytochemistry experiments. While in both cell models the most represented PI-PLC isoforms were beta4, gamma1, delta4, and epsilon, isoforms PI-PLC beta2 and delta3 were not detected. Moreover, in primary astrocyte cultures PI-PLC delta3 resulted well expressed in C6 cells but was absent in astrocytes. Immunocytochemistry performed with antibodies against specific PLC isoforms substantially confirmed this pattern of expression both in astrocytes and C6 glioma cells. In particular while some isoenzymes (namely isoforms beta3 and beta4) resulted mainly nuclear, others (isoforms delta4 and epsilon) were preferentially localized at cytoplasmic and plasma membrane level.
 ...
PMID:Expression of phosphoinositide-specific phospholipase C isoenzymes in cultured astrocytes. 1706 84


1 2 3 Next >>