Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clozapine (CZP), a dibenzodiazepine derivative with a piperazinyl side chain, is in clinical use as an antipsychotic drug. This study investigated the effect of CZP on the modulation of the PI3K/Akt/GSK-3beta pathway in PTEN-negative U-87MG glioblastoma cells. Treatment with CZP rapidly inhibited the basal and EGF-induced phosphorylation of Akt. The inhibition of Akt resulted in the dephosphorylation of GSK-3beta and increased GSK-3beta kinase activity. A voltage-sensitive Ca(2+) channel blocker and calmodulin (CaM) antagonists inhibited Akt phosphorylation, whereas elevation of the intracellular Ca(2+) concentration prevented CZP-induced dephosphorylation of Akt and GSK-3beta, suggesting that Ca(2+)/CaM participates in the inhibition of Akt by CZP in U-87MG cells. In addition, similar to LY294002, CZP arrested cell cycle progression at G0/G1 phase, which was accompanied by decreased expression of cyclin D1. The reduction in the cyclin D1 level induced by CZP was abrogated by the inhibition of GSK-3beta, the inhibition of proteasome-dependent proteolysis, or an increase in the intracellular Ca(2+) concentration. These results suggest that the antipsychotic drug CZP modulates the PI3K/Akt/GSK-3beta pathway by counteracting Ca(2+)/CaM in PTEN-negative U-87MG glioblastoma cells.
 ...
PMID:Clozapine, a neuroleptic agent, inhibits Akt by counteracting Ca2+/calmodulin in PTEN-negative U-87MG human glioblastoma cells. 1654 21

The transcription factor nuclear factor-kappaB (NF-kappaB) is a key regulator of stress-induced transcriptional activation and has been implicated in mediating primary or acquired apoptosis resistance in various cancers. In the present study, we therefore investigated the role of NF-kappaB in regulating apoptosis in malignant glioma, a prototypic tumor refractory to current treatment approaches. Here, we report that constitutive NF-kappaB DNA-binding activity was low or moderate in eight different glioblastoma cell lines compared to Hodgkin's lymphoma cells, known to harbor aberrant constitutive NF-kappaB activity. Specific inhibition of NF-kappaB by overexpression of inhibitor of kappaB (IkappaB)alpha superrepressor did not enhance spontaneous apoptosis of glioblastoma cells. Also, overexpression of IkappaBalpha superrepressor had no significant impact on apoptosis induced by two prototypic classes of apoptotic stimuli, that is, chemotherapeutic drugs or death-inducing ligands such as TNF-related apoptosis inducing ligand (TRAIL), which are known to trigger NF-kappaB activation as part of a cellular stress response. Similarly, inhibition of NF-kappaB by the proteasome inhibitor MG132 did not increase doxorubicin (Doxo)-induced apoptosis of glioblastoma cells, although it prevented DNA binding of NF-kappaB complexes in response to Doxo. Interestingly, proteasome inhibition significantly sensitized glioblastoma cells for TRAIL-induced apoptosis. These findings indicate that the characteristic antiapoptotic function of NF-kappaB reported for many cancers is not a primary feature of glioblastoma and thus, specific NF-kappaB inhibition may not be effective for chemosensitization of glioblastoma. Instead, proteasome inhibitors, which enhanced TRAIL-induced apoptosis in an NF-kappaB-independent manner, may open new perspectives to increase the efficacy of TRAIL-based regimens in glioblastoma, which warrants further investigation.
 ...
PMID:NF-kappaB-independent sensitization of glioblastoma cells for TRAIL-induced apoptosis by proteasome inhibition. 1690 19

The ellipticinium and its derivatives have been studied as anti-cancer agents with preferentially cyto-toxicity to the brain tumor cell lines. During the course of our study to determine whether an ellipticine derivative, API59-Cl would sensitize radio-resistant U87 glioblastoma cells to radiation, we found that it reduced the level of p27, a cyclin-dependent kinase inhibitor. API59-Cl induced a dose and time dependent p27 reduction in U87 cells. The compound-induced p27 reduction was also seen in three additional glioblastoma lines, T98G, U251 and U118 as well as in mouse embryonic fibroblasts. Mechanistic study of API59-Cl mediated p27 reduction revealed that it was not due to an altered p27 transcription, rather due to a shortened protein half-life as a result of enhanced p27 degradation. Indeed, API59-Cl induced p27 degradation was dependent on ubiquitin-proteasome pathway, particularly E3 ubiquitin ligase component, Skp2, but not Cullin-4A/4B, and can be largely blocked by proteasome inhibitors MG132 or PS341. Finally, we demonstrated that API59-Cl inhibited U87 cell growth with an IC50 of 1.7 muM, which is independent of its p27 degrading activity. This is the first report, to our knowledge, that the ellipticinium class of small molecule compounds promotes p27 degradation via ubiquitin-proteasome pathway. The finding could provide a new tool to further understand the mechanism of p27 degradation.
 ...
PMID:p27 degradation by an ellipticinium series of compound via ubiquitin-proteasome pathway. 1731 89

Ansamycins exert their effects by binding heat shock protein 90 (Hsp90) and targeting important signalling molecules for degradation via the proteasome pathway. We wanted to study the effect of geldanamycin (GA) and its derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG) on glioblastoma cell lines. We show that these cells are growth inhibited by ansamycins by being arrested in G(2)/M and, subsequently, cells undergo apoptosis. The protein levels of cell division cycle 2 (cdc2) kinase and cell division cycle 25c (cdc25c) were downregulated upon GA and 17-AAG treatment and cdc2 kinase activity was inhibited. However, other proteins involved in the G(2)/M checkpoint were not affected. The cdc2 and cdc25c mRNA levels did not show significant differences upon ansamycin treatment, but the stability of cdc2 protein was reduced. The association of cdc2 and cdc25c with p50(cdc37), an Hsp90 co-chaperone, decreased, but the interaction of cdc2 and cdc25c with the Hsp70 co-chaperone increased after ansamycin treatment. Proteasome inhibitors were able to rescue the cdc2 downregulation, but not the cdc25c reduction. However, calpain inhibitors were able to rescue the cdc25c downregulation, suggesting that cdc25c is proteolysed by calpains in the presence of ansamycins, and not by the proteasome. We conclude that ansamycins downregulate cdc2 and cdc25c by two different mechanisms.
 ...
PMID:Inhibition of Hsp90 function by ansamycins causes downregulation of cdc2 and cdc25c and G(2)/M arrest in glioblastoma cell lines. 1752 41

The death-associated protein Daxx is a multifunctional factor that regulates a variety of cellular processes, including transcription and apoptosis. Several previous reports have indicated that Daxx is induced upon oxidative stress and is then subjected to phosphorylation-based functional modification. However, the precise molecular events underlying these phosphorylation events remain largely unknown. We report in our current study that the peptidyl-prolyl isomerase Pin1 is highly overexpressed in malignant human gliomas and inhibits Daxx-mediated cellular apoptosis. The targeted inhibition of Pin1 by small interfering RNA in A172 glioblastoma cells significantly enhances the apoptotic response induced by hydrogen peroxide or stimulatory Fas antibodies. This is in turn accompanied by the increased induction of Daxx and the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase pathway. Furthermore, Pin1 binds to the phosphorylated Ser178-Pro motif in the Daxx protein, and Pin1 overexpression results in the rapid degradation of Daxx via the ubiquitin-proteasome pathway. Moreover, a Daxx-S178A mutant, which cannot interact with Pin1, demonstrates higher proapoptotic activity and is refractory to Pin1-mediated antiapoptotic effects. We further found that the expression levels of Pin1 inversely correlate with the degree of Daxx nuclear accumulation in human glioblastoma tissues. These results together indicate that Pin1-mediated prolyl isomerization plays an important role in the negative regulation of Daxx and thereby inhibits the oxidative stress-induced cellular apoptotic response, particularly in malignant tumor cells where Pin1 is often overexpressed.
 ...
PMID:A suppressive role of the prolyl isomerase Pin1 in cellular apoptosis mediated by the death-associated protein Daxx. 1793 71

Little is known about the factors that influence the proteasome structures in cells and their activity, although this could be highly relevant to cancer therapy. We have previously shown that, within minutes, irradiation inhibits substrate degradation by the 26S proteasome in most cell types. Here, we report an exception in U87 glioblastoma cells transduced to express the epidermal growth factor receptor vIII (EGFRvIII) mutant (U87EGFRvIII), which does not respond to irradiation with 26S proteasome inhibition. This was assessed using either a fluorogenic substrate or a reporter gene, the ornithine decarboxylase degron fused to ZsGreen (cODCZsGreen), which targets the protein to the 26S proteasome. To elucidate whether this was due to alterations in proteasome composition, we used quantitative reverse transcription-PCR to quantify the constitutive (X, Y, Z) and inducible 20S subunits (Lmp7, Lmp2, Mecl1), and 11S (PA28alpha and beta) and 19S components (PSMC1 and PSMD4). U87 and U87EGFRvIII significantly differed in expression of proteasome subunits, and in particular immunosubunits. Interestingly, 2 Gy irradiation of U87 increased subunit expression levels by 16% to 324% at 6 hours, with a coincident 30% decrease in levels of the proteasome substrate c-myc, whereas they changed little in U87EGFRvIII. Responses similar to 2 Gy were seen in U87 treated with a proteasome inhibitor, NPI0052, suggesting that proteasome inhibition induced replacement of subunits independent of the means of inhibition. Our data clearly indicate that the composition and function of the 26S proteasome can be changed by expression of the EGFRvIII. How this relates to the increased radioresistance associated with this cell line remains to be established.
 ...
PMID:Epidermal growth factor receptor vIII expression in U87 glioblastoma cells alters their proteasome composition, function, and response to irradiation. 1833 49

Previous studies suggest the expression of UbcH10 gene, that codes for a protein belonging to the ubiquitin-conjugating enzyme family, as a valid indicator of the proliferative and aggressive status of tumors of different origin. Therefore, to look for possible tools to be used as diagnostic markers in astrocytic neoplasias, we investigated UbcH10 expression in normal brain, gliosis and low-grade and high-grade astrocytic tumors by immunohistochemistry. UbcH10 expression was observed in low-grade astrocytoma and in glioblastoma. Our data indicate a clear correlation between UbcH10 expression and the histological grade of the astrocytic tumors. Moreover, the analysis of UbcH10 expression allows the differentiation between gliotic and malignant tissues. Finally, since proteasome inhibitors have recently been considered as possible drugs in the chemotherapy of various tumors, our results would suggest new perspectives for the treatment of brain malignancies based on the suppression of the UbcH10 function.
 ...
PMID:Analysis of UbcH10 expression represents a useful tool for the diagnosis and therapy of astrocytic tumors. 1866 37

Resistance to apoptosis is one reason for the poor response of malignant brain tumors to therapy. The PPARgamma-modulating drug Troglitazone downregulates the anti-apoptotic FLIP protein and sensitizes glioblastoma cells to apoptosis induced by the death ligand TRAIL. To investigate the molecular basis of an experimental combination therapy for malignant gliomas with TRAIL and Troglitazone, we investigated the Troglitazone-induced signaling cascades and the expression of TRAIL receptors and FLIP in malignant gliomas. Troglitazone downregulated the FLIP protein through accelerated ubiquitin/proteasome-dependent degradation, which might be mediated by a Troglitazone-induced increase in reactive oxygen species. Moreover, Troglitazone induced the phosphorylation of the MAP kinase ERK1/2 as well as of the BAD protein. Inhibition of either PPARgamma or MEK1/2 blocked the Troglitazone-mediated phosphorylation of BAD and further increased the synergistic induction of glioma cell death by TRAIL and Troglitazone. Immunohistochemical analysis demonstrated that FLIP and TRAIL-R2 were significantly higher expressed in anaplastic (WHO grade III) than in diffuse (WHO grade II) gliomas. High FLIP and low TRAIL-R2 expression levels were associated with a poor prognosis of patients. Our findings warrant a further pre-clinical evaluation of an experimental anti-glioma therapy with TRAIL and Troglitazone, potentially in conjunction with a MAP kinase inhibitor.
 ...
PMID:Troglitazone-mediated sensitization to TRAIL-induced apoptosis is regulated by proteasome-dependent degradation of FLIP and ERK1/2-dependent phosphorylation of BAD. 1915 81

The anticancer potency of green tea and its individual components is being intensely investigated, and some cancer patients already self-medicate with this "miracle herb" in hopes of augmenting the anticancer outcome of their chemotherapy. Bortezomib (BZM) is a proteasome inhibitor in clinical use for multiple myeloma. Here, we investigated whether the combination of these compounds would yield increased antitumor efficacy in multiple myeloma and glioblastoma cell lines in vitro and in vivo. Unexpectedly, we discovered that various green tea constituents, in particular (-)-epigallocatechin gallate (EGCG) and other polyphenols with 1,2-benzenediol moieties, effectively prevented tumor cell death induced by BZM in vitro and in vivo. This pronounced antagonistic function of EGCG was evident only with boronic acid-based proteasome inhibitors (BZM, MG-262, PS-IX), but not with several non-boronic acid proteasome inhibitors (MG-132, PS-I, nelfinavir). EGCG directly reacted with BZM and blocked its proteasome inhibitory function; as a consequence, BZM could not trigger endoplasmic reticulum stress or caspase-7 activation, and did not induce tumor cell death. Taken together, our results indicate that green tea polyphenols may have the potential to negate the therapeutic efficacy of BZM and suggest that consumption of green tea products may be contraindicated during cancer therapy with BZM.
 ...
PMID:Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. 1974 81

Hypoxia and hypoxia inducible factor-1alpha (HIF-1alpha) play a critical role in glioblastoma (GBM) which is characterized by highly aggressive and widespread cell invasion into adjacent normal brain tissue. The purpose of this study was to investigate the effect of the novel aminothiazole com-pound SNS-032 in glioblastoma cell invasion under hypoxic condition. SNS-032 is a potent and selective inhibitor of cyclin-dependent kinases 2, 7 and 9 and inhibits both cell cycle and transcription. We analyzed the effect of SNS-032 (0.5 microM) on HIF-1alpha expression and its major trans-regulating factors including COX-2, VEGF, MMP-2 and uPAR that are involved in cellular invasion in tumor hypoxia. Our observations demonstrate SNS-032: i) inhibited hypoxia-induced U87MG cell invasion and among all the other inhibitors tested, SNS-032 is the most effective, ii) blocked HIF-1alpha mediated transcription of COX-2, MMP-2, VEGF and uPAR expression in U87MG cells in response to hypoxia, iii) blocked HIF-1alpha expression by a proteasome independent pathway. The effects were similar to those observed with HIF-1alpha siRNA which prevented cellular invasion by blocking HIF-1alpha expression and its downstream effectors. Taken together, our data suggest that SNS-032 prevents hypoxia-mediated U87MG cell invasion by blocking the expression of HIF-1alpha and its trans-regulating factors. Our results present an opportunity in controlling highly invasive tumors such as glioblastoma using this novel class of compounds.
 ...
PMID:SNS-032 prevents hypoxia-mediated glioblastoma cell invasion by inhibiting hypoxia inducible factor-1alpha expression. 1928 62


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>