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)

The PTEN tumor suppressor acts as a phosphatase for phosphatidylinositol-3,4,5-trisphosphate (PIP3) [1, 2]. We have shown previously that PTEN negatively controls the G1/S cell cycle transition and regulates the levels of p27(KIP1), a CDK inhibitor [3, 4]. Recently, we and others have identified an ubiquitin E3 ligase, the SCF(SKP2) complex, that mediates p27 ubiquitin-dependent proteolysis [5-7]. Here we report that PTEN and the PI 3-kinase pathway regulate p27 protein stability. PTEN-deficiency in mouse embryonic stem (ES) cells causes a decrease of p27 levels with concomitant increase of SKP2, a key component of the SCF(SKP2) complex. Conversely, in human glioblastoma cells, ectopic PTEN expression leads to p27 accumulation, which is accompanied by a reduction of SKP2. We found that ectopic expression of SKP2 alone is sufficient to reverse PTEN-induced p27 accumulation, restore the kinase activity of cyclin E/CDK2, and partially overcome the PTEN-induced G1 cell cycle arrest. Consistently, recombinant SCF(SKP2) complex or SKP2 protein alone can rescue the defect in p27 ubiquitination in extracts prepared from cells treated with a PI 3-kinase inhibitor. Our findings suggest that SKP2 functions as a critical component in the PTEN/PI 3-kinase pathway for the regulation of p27(KIP1) and cell proliferation.
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PMID:PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27(KIP1) through the ubiquitin E3 ligase SCF(SKP2). 1125 Jan 55

New therapeutic strategies are needed to improve survival in glioblastoma (GBM) the most malignant astrocytic tumor. We evaluated: a) the genetic status of 22 GBMs by comparative genomic hybridization (CGH); b) the specific role of mutation and/or homozygous deletion of PTEN in the genesis of GBM; and c) the possible therapeutic role of PTEN against GBM, in vitro. CGH demonstrated that the most frequent region of gain was at chromosome 7p, whereas the most frequent losses occurred at chromosomes 10q and 13q. Losses at chromosome 10 were found in 36% of patients, and PTEN was mutated in 27% of the 22 GBMs, including 4 point mutations and 2 homozygous deletions. The possible therapeutic role of PTEN in GBM was also studied in a system based on retroviral infection of the GBM cell line A172, homozygously deleted at the PTEN locus. A172 growth and proliferation rate were reduced by 50% after PTEN transduction. Moreover, we showed that inhibition of cell growth occurred through the PI3K/Akt/p27 pathway. Our findings suggest that PTEN participates in the genesis of GBM, and might be further studied as a candidate therapeutic agent in other testing systems.
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PMID:Genetic profile, PTEN mutation and therapeutic role of PTEN in glioblastomas. 1237 Jul 66

Alterations of the epidermal growth factor receptor (EGFR) gene are common in some forms of cancer and the most frequent is a deletion of exons 2-7. We have previously shown that this mutant receptor, called DeltaEGFR, confers enhanced tumorigenicity to glioblastoma cells through elevated proliferation and reduced apoptotic rates of the tumor cells in vivo. To understand the molecular mechanisms that underlie DeltaEGFR-enhanced proliferation, we examined the gene products that control cell cycle progression. We found that levels of the cyclin-dependent kinase (CDK) inhibitor, p27, were lower in U87MG.DeltaEGFR tumors than in parental U87MG or control U87MG.DK tumors. Consequently, CDK2-cyclin A activity was also elevated, concomitant with the RB protein hyperphosphorylation. In addition, activated phosphatidylinositol 3-kinase (PI3-K) and phosphorylated Akt levels were also elevated in the U87MG.DeltaEGFR tumors. U87MG.DeltaEGFR cells failed to arrest in G(1) in response to serum starvation in vitro and while maintaining high levels of PI3-K activity and hyperphosphorylated RB. Treatment of U87MG.DeltaEGFR cells with LY294002, a PI3-K inhibitor, caused reduced levels of phosphorylated Akt and concomitantly up-regulated levels of p27. Expression of a kinase dead dominant-negative Akt mutant in the U87MG.DeltaEGFR cells similarly resulted in up-regulation of p27 and down-regulation of tumorigenicity in vivo. These results suggest that the constitutively active DeltaEGFR can enhance cell proliferation in part by down-regulation of p27 through activation of the PI3-K/Akt pathway. This pathway may represent another therapeutic target for treatment of those aggressive glioblastomas expressing DeltaEGFR.
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PMID:Mutant epidermal growth factor receptor signaling down-regulates p27 through activation of the phosphatidylinositol 3-kinase/Akt pathway in glioblastomas. 1243 78

Glioblastoma (GBM) remains one of the most challenging solid cancers to treat due to its highly proliferative, angiogenic and invasive nature. The small molecule CDK inhibitor, flavopiridol, has demonstrated antitumor activity in human xenograft models and is currently in clinical trials showing efficacy in patients with advanced disease. We have developed an experimental animal model using the murine glioma GL261 cells as a novel in vivo system to screen potential therapeutic agents for GBM. Results of in vitro testing demonstrate that flavopiridol has several relevant clinical characteristics such as its ability to: 1. inhibit cell growth; 2. inhibit cell migration; 3. decrease expression of cyclin D1, CDK4 and p21; 4. induce apoptosis in cells with high levels of p27 expression; and 5. decrease the expression of the anti-apoptotic protein Bcl-2. The mechanism by which flavopiridol induces apoptosis is mitochondrial-mediated. We demonstrate by electron microscopy and immunohistochemistry that drug treatment induces mitochondrial damage that was accompanied by the release of cytochrome c into the cytosol together with the translocation of apoptosis inducing factor (AIF) into the nucleus. This finding in murine glioma cells differs from the mechanism of flavopiridolinduced cell death reported by us for human glioma cells (Alonso et al., Mol Cancer Ther 2003; 2:139) where drug treatment induced a caspase- and cytochrome c-independent pathway in the absence of detectable damage to mitochondria. In apoptotic human glioma cells only translocation of AIF into the nucleus occurred. Thus, the same drug kills different types of glioma cells by different mitochondrial-dependent pathways.
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PMID:Flavopiridol induces mitochondrial-mediated apoptosis in murine glioma GL261 cells via release of cytochrome c and apoptosis inducing factor. 1273 34

Glioblastoma multiforme is the most common malignant brain tumor in adults, and it is among the most lethal of all cancers. Recent studies have shown that ligand activation of peroxisome proliferator-activated receptor (PPAR)-gamma can induce differentiation and inhibit proliferation of several cancer cells. In this study, we have investigated whether one PPARgamma ligand in particular, ciglitazone, inhibits cell viability and, additionally, whether it affects the cell cycle and apoptosis of human glioblastoma cell lines T98G, U-87 MG, A172, and U-118 MG. All glioblastoma cell lines were found to express PPARgamma protein, and following treatment with ciglitazone, localization was unchanged. Ciglitazone inhibited viability in a dose-dependent manner in all four tested glioblastoma cells after 24 h of treatment. Analysis of the cell cycle showed arrest in the G(1) phase and partial block in G(2)/M phase of the cell cycle. Cyclin D1 and cyclin B expression was decreased. Phosphorylation of Rb protein dropped as well. We found that ciglitazone was followed by increased expression of p27(Kip1) and p21(Waf1/Cip1). It also led to apoptosis induction: bax expression in T98G was elevated. Expression of the antiapoptotic protein bcl-2 was reduced in U-118 MG and U-87 MG and showed a slight decrease in A172 cells. Flow cytometry confirmed the induction of apoptosis. Moreover, PPARgamma ligand decreased telomerase activity in U-87 MG and U-118 MG cell lines. Our results demonstrate that ciglitazone inhibits the viability of human glioblastoma cell lines via induction of apoptosis; as a result, this ligand may offer potential new therapy for the treatment of central nervous system neoplasms.
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PMID:The synthetic ligand of peroxisome proliferator-activated receptor-gamma ciglitazone affects human glioblastoma cell lines. 1498 21

The PTEN tumor suppressor gene is a frequent target of somatic mutation, particularly in glioblastoma multiform and prostate cancer. The expression of PTEN in PTEN-mutant glioblastoma cells leads to a cell cycle arrest in G(0)/G(1) that is mediated at least partially by increased p27(kip1) levels. Here we show that p27(kip1) is not regulated by transcriptional control but that p27(kip1) protein shows increased stability after inhibition of the phosphoinositide (PI) 3-kinase pathway. Because p27(kip1) protein stability is known to be regulated by phosphorylation, we have examined modifications in the phosphorylation pattern after PI 3-kinase inhibition. Biochemical evidence suggests that p27(kip1) is phosphorylated on several serine residues, including Ser-10 and Ser-178, but that phosphorylation is unaltered by PI 3-kinase activity. This is further confirmed by the inducible expression of p27(kip1) phosphorylation site mutants, suggesting that p27(kip1) is destabilized in a phosphorylation-independent manner by the PI 3-kinase pathway at the G(1)/S transition.
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PMID:Phosphorylation-independent stabilization of p27kip1 by the phosphoinositide 3-kinase pathway in glioblastoma cells. 1554 3

We have reported previously that the expression of focal adhesion kinase (FAK) is elevated in glioblastomas and that expression of FAK promotes the proliferation of glioblastoma cells propagated in either soft agar or in the C.B.17 severe combined immunodeficiency (scid) mouse brain. We therefore determined the effect of FAK on cell cycle progression in these cells. We found that overexpression of wild-type FAK promoted exit from G(1) in monolayer cultures of glioblastoma cells, enhanced the expression of cyclins D1 and E while reducing the expression of p27(Kip1) and p21(Waf1), and enhanced the kinase activity of the cyclin D1-cyclin-dependent kinase-4 (cdk4) complex. Transfection of the monolayers with a FAK molecule in which the autophosphorylation site is mutated (FAK397F) inhibited exit from G(1) and reduced the expression of cyclins D1 and E while enhancing the expression of p27(Kip1) and p21(Waf1). Small interfering RNA (siRNA)-mediated down-regulation of cyclin D1 inhibited the enhancement of cell cycle progression observed on expression of wild-type FAK, whereas siRNA-mediated down-regulation of cyclin E had no effect. siRNA-mediated down-regulation of p27(Kip1) overcame the inhibition of cell cycle progression observed on expression of FAK397F, whereas down-regulation of p21(Waf1) had no effect. These results were confirmed in vivo in the scid mouse brain xenograft model in which propagation of glioblastoma cells expressing FAK397F resulted in a 50% inhibition of tumor growth and inhibited exit from G(1). Taken together, our results indicate that FAK promotes proliferation of glioblastoma cells by enhancing exit from G(1) through a mechanism that involves cyclin D1 and p27(Kip1).
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PMID:p27Kip1 and cyclin D1 are necessary for focal adhesion kinase regulation of cell cycle progression in glioblastoma cells propagated in vitro and in vivo in the scid mouse brain. 1555 80

S-phase kinase associated protein (Skp) 2 is an F-box protein required for substrate recognition of the SCF(Skp2) ubiquitin ligase complex. Skp2 is often overexpressed in transformed cells and in various types of tumors. Downregulation or inhibition of Skp2 inhibits growth of breast cancer cells and small-cell lung carcinoma cells. We downregulated Skp2 in T98G glioblastoma cells using small interfering RNA (siRNA). Downregulation induced p27 and caused growth arrest and apoptosis. Downregulation of both Skp2 and p27 increased apoptosis synergistically. Cyclin E levels and cyclin E-CDK2 kinase activity increased dramatically when both Skp2 and p27 were downregulated. Coincidently, Bcl-2 but not Bcl-xL expression decreased, and caspase-3 was activated. Inhibition of cyclin E-CDK2 kinase activity by forced expression of p21 reversed these effects. Moreover, stable expression of Bcl-2 also abrogated apoptosis induced by downregulation of Skp2 and p27. We suggest that Skp2 in tumor cells suppresses apoptosis through Bcl-2 expression, potentially through regulation of cyclin E-CDK2 activity.
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PMID:Downregulation of Skp2 and p27/Kip1 synergistically induces apoptosis in T98G glioblastoma cells. 1560 73

The naturally occurring mutated form of the epidermal growth factor receptor, deltaEGFR (also named EGFRvIII and de2-7EGFR), greatly enhances glioblastoma (GBM) cell growth in vivo through several activities, such as down-regulating p27 and up-regulating BclX(L) while increasing signaling through the RAS-MAPK and PI3-K cascades. More than half of GBMs, especially of the de novo type, overexpress EGFR, and 50%-70% of these express deltaEGFR. However, little is known about the distribution of deltaEGFR-expressing tumor cells within surgical specimens. In order to address this clinically important issue, we performed immunohistochemical analyses of 53 GBMs obtained during surgery using the anti- deltaEGFR monoclonal antibody, DH8.3. We also simultaneously analyzed wild-type EGFR expression in these tissues using the anti-EGFR monoclonal antibody, EGFR.113. deltaEGFR and wild-type EGFR expression were observed in 20/53 (38%) and 29/53 (55%), respectively. Nineteen (95%) of the deltaEGFR-positive tumors also expressed wild-type EGFR; one case was deltaEGFR-positive but wild-type EGFR-negative. In 13/20 (65%) of the deltaEGFR-positive tumors, tumor cells were scattered diffusely within the tumors, 6/20 showed geographical distribution of deltaEGFR-positive tumor cells, and one case showed homogeneous staining. In the wild-type EGFR-positive cases, almost all tumor cells expressed EGFR. The differential distribution of cells expressing the two receptors observed here may suggest either that deltaEGFR arises at a low frequency from wild-type EGFR-expressing cells, perhaps during the process of gene amplification, or that there is a paracrine-type of interaction between them.
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PMID:Immunohistochemical analysis of the mutant epidermal growth factor, deltaEGFR, in glioblastoma. 1570 Aug 33

Lovastatin (an HMG-CoA reductase inhibitor) and troglitazone (a PPAR-gamma agonist) have been intensively studied prospectively for their application in cancer treatment. However, clinical trials of lovastatin or troglitazone in cancer treatment resulted in only limited responses. To improve their efficacy, lovastatin and troglitazone have, respectively, been tried to combine with other anticancer agents with varied outcomes. In our study, we found a dramatic synergism between lovastatin and troglitazone in anticancer at clinically achievable concentrations. This synergism was found in far majority of cell lines tested including DBTRG 05 MG (glioblastoma) and CL1-0 (lung). This amazing synergism was accompanied by synergistic modulation of E2F-1 and p27(Kip1), which were reported to mediate the anticancer activities of lovastatin and troglitazone, respectively, and other cell cycle regulating proteins such as CDK2, cyclin A and RB phosphorylation status. With this dramatic combination effect of lovastatin and troglitazone, a promising regimen of cancer therapy may be materialized in the future.
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PMID:Dramatic synergistic anticancer effect of clinically achievable doses of lovastatin and troglitazone. 1609 29


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