Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular Endothelial Growth Factor (VEGF)/Vascular Permeability Factor plays an important role in angiogenesis and cell proliferation of cancer cells. Glioblastoma cells are most malignant and show resistance to radiation therapy inducing VEGF to cause angiogenesis and brain edema. In the present study, the regulatory mechanism of the expression of VEGF by ionizing radiation was studied in three human glioblastoma cells. Induction of VEGF mRNA by ionizing radiation was dependent on dose and incubation time. Activator protein-1 (AP-1) was activated by 10 Gy of ionizing radiation in 1 h in T98G glioblastoma cells on an electrophoretic mobility shift assay. We constructed chimeric genes containing various regions of the VEGF promoter gene and the coding region for chloramphenicol acetyltransferase (CAT) and transiently transfected them to T98G cells. CAT assay with the VEGF promoter gene containing an AP-1 site demonstrated that the promoter activity of the VEGF gene was enhanced by ionizing radiation. Immunological analysis of the activity of mitogen-activated protein kinase, ERK1/2, showed that this activity is up-regulated by ionizing radiation. These results suggest that ERK1/2 pathway is involved in the up-regulation of VEGF expression ionizing radiation mediated by AP-1, which may lead to further neovascularization and proliferation of glioblastoma cells resistant to radiation therapy.
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PMID:Mitogen-activated protein kinase, ERK1/2, is essential for the induction of vascular endothelial growth factor by ionizing radiation mediated by activator protein-1 in human glioblastoma cells. 1088 23

Major advances in molecular biology, cellular biology and genomics have substantially improved our understanding of cancer. Now, these advances are being translated into therapy. Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer patients. Glioblastoma (GBM), the most common brain cancer of adults, is highly suited for this new approach. GBMs commonly overexpress the oncogenes EGFR and PDGFR, and contain mutations and deletions of tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the P13K/Akt and Ras/MAPK pathways, which provide targets for therapy. In this paper, we review the ways in which molecular therapies are being applied to GBM patients, and describe the tools of these approaches: pathway inhibitors, monoclonal antibodies and oncolytic viruses. We describe strategies to: i) target EGFR, its ligand-independent variant EGFRvIII, and PDGFR on the cell surface, ii) inhibit constitutively activate RAS/MAPK and PI3K/Akt signaling pathways, iii) target TP53 mutant tumors, and iv) block GBM angiogenesis and invasion. These new approaches are likely to revolutionize the treatment of GBM patients. They will also present new challenges and opportunities for neuropathology.
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PMID:Targeted molecular therapy of GBM. 1258 May 45

The present study uses cell-based screening assays to assess the anticancer effects of targeting phosphatidylinositol 3-kinase-regulated integrin-linked kinase (ILK) in combination with small-molecule inhibitors of Raf-1 or mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK). The objective was to determine if synergistic interactions are achievable through the use of agents targeting two key cell signaling pathways involved in regulating glioblastoma cancer. The phosphatidylinositol 3-kinase/protein kinase B (PKB)/Akt and the Ras/MAPK pathway were targeted for their involvement in cell survival and cell proliferation, respectively. The glioblastoma cell lines U87MG, SF-188, and U251MG were transiently transfected with an antisense oligonucleotide targeting ILK (ILKAS) alone or in combination with the Raf-1 inhibitor GW5074 or with the MEK inhibitor U0126. Dose and combination effects were analyzed by the Chou and Talalay median-effect method and indicated that combinations targeting ILK with either Raf-1 or MEK resulted in a synergistic interaction. Glioblastoma cells transfected with ILKAS exhibited reduced levels of ILK and phosphorylated PKB/Akt on Ser473 but not PKB/Akt on Thr308 as shown by immunoblot analysis. These results were confirmed using glioblastoma cells transfected with ILK small interfering RNA, which also suggested enhanced gene silencing when used in combination with U0126. U87MG glioblastoma cells showed a 90% (P < 0.05) reduction in colony formation in soft agar with exposure to ILKAS in combination with GW5074 compared with control colonies. A substantial increase in Annexin V-positive cells as determined by using fluorescence-activated cell sorting methods were seen in combinations that included ILKAS. Combinations targeting ILK and components of the Ras/MAPK pathway result in synergy and could potentially be more effective against glioblastoma cancer than monotherapy.
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PMID:Combined inhibition of the phosphatidylinositol 3-kinase/Akt and Ras/mitogen-activated protein kinase pathways results in synergistic effects in glioblastoma cells. 1654 79

Glioblastomas are intrinsically resistant to conventional radiation therapy. The present study investigated the possibility that the tyrosine kinase inhibitor, imatinib, could enhance radiation sensitivity and influence proliferative recovery after irradiation in glioblastoma cells. Radiosensitivity was evaluated by clonogenic survival; apoptotic cell death was evaluated using flow cytometric analysis; proliferative recovery was monitored based on viable cell number subsequent to radiation-induced growth arrest; activation of p44/42 MAPK was based on phosphorylation of the protein. Glioblastoma cells pretreated with imatinib demonstrated an enhanced sensitivity to radiation. Imatinib also delayed proliferative recovery in irradiated glioblastoma cells. Imatinib promoted suppression of p44/42 MAPK signaling both when added prior to and post-irradiation. Increased sensitivity to radiation and delayed proliferative recovery in irradiated glioblastoma cells exposed to imatinib may be a consequence of the capacity of imatinib to interfere with p44/42 MAPK kinase signaling. Imatinib may prove to have clinical utility as a neoadjuvant and adjuvant in the treatment of glioblastomas that receive radiation therapy.
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PMID:Enhancement of radiation sensitivity, delay of proliferative recovery after radiation and abrogation of MAPK (p44/42) signaling by imatinib in glioblastoma cells. 1682 Aug 83

Glioblastoma is the most malignant and common brain tumor. To promote their growth, these glioma cells secrete a variety of soluble factors including plasminogen activator inhibitor-1 (PAI-1), which functions as an inhibitor of plasminogen activators. We report here with the basis of microarray gene expression analysis that CXCR4 expressing glioma cells are capable of expressing PAI-1 mRNA and protein upon CXCL12 stimulation. Pretreatment with U0126, an inhibitor of mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2, abrogated CXCL12-induced PAI-1 expression. Pertussis toxin (PTX), an inhibitor of Galpha(i) proteins, also had inhibitory effects, indicating that the activation of Galpha(i) and ERK MAPK are required for this response. Interestingly, CXCL12 showed additive effects with another PAI-1 inducers, tumor necrosis factor (TNF)-alpha and/or tumor growth factor (TGF)-beta1, in increasing PAI-1 expression. These results indicate that CXCL12/CXCR4 signaling in glioma cells may be another mechanism for these cells to express PAI-1, which may be involved in angiogenesis and tumor invasion in brain tumors.
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PMID:CXCL12-mediated induction of plasminogen activator inhibitor-1 expression in human CXCR4 positive astroglioma cells. 1933 86

Glioblastomas (GBMs) are the most frequent and malignant brain tumors in adults. Glucocorticoids (GCs) are routinely used in the treatment of GBMs for their capacity to reduce the tumor-associated edema. Few in vitro studies have suggested that GCs inhibit the migration and invasion of GBM cells through the induction of MAPK phosphatase 1 (MKP-1). Macrophage migration inhibitory factor (MIF), an endogenous GC antagonist is up-regulated in GBMs. Recently, MIF has been involved in tumor growth and migration/invasion and specific MIF inhibitors have been developed on their capacity to block its enzymatic tautomerase activity site. In this study, we characterized several glioma cell lines for their MIF production. U373 MG cells were selected for their very low endogenous levels of MIF. We showed that dexamethasone inhibits the migration and invasion of U373 MG cells, through a glucocorticoid receptor (GR)- dependent inhibition of the ERK1/2 MAPK pathway. Oppositely, we found that exogenous MIF increases U373 MG migration and invasion through the stimulation of the ERK1/2 MAP kinase pathway and that this activation is CD74 independent. Finally, we used the Hs 683 glioma cells that are resistant to GCs and produce high levels of endogenous MIF, and showed that the specific MIF inhibitor ISO-1 could restore dexamethasone sensitivity in these cells. Collectively, our results indicate an intricate pathway between MIF expression and GC resistance. They suggest that MIF inhibitors could increase the response of GBMs to corticotherapy.
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PMID:The dexamethasone-induced inhibition of proliferation, migration, and invasion in glioma cell lines is antagonized by macrophage migration inhibitory factor (MIF) and can be enhanced by specific MIF inhibitors. 1975 12

Targeted molecular therapies against the epidermal growth factor receptor (EGFR) are novel, promising and potentially radiosensitising therapeutic approaches in the treatment of glioblastoma, a highly malignant and treatment-refractory brain tumour. Despite a solid rational basis, specific EGFR inhibition has rendered only disappointing clinical results to date. We therefore evaluated the efficacy of additional inhibition of human epidermal growth factor receptor 2 (HER2), the 'non-autonomous amplifier' of EGFR signalling. Glioblastoma cells (LN-18, LN-229) with different co-expression levels of EGFR and HER2 were treated with specific EGFR and bispecific EGFR/HER2 tyrosine kinase inhibitors (TKIs) (AG1478, AEE788) and experimental radiotherapy, followed by assessment of growth inhibition. Activity of the major downstream signalling pathways Akt and MAPK was determined by immunoblotting. EGFR-overexpressing LN-18 cells (EGFR++++/HER2+) showed resistance and HER2-overexpressing LN-229 cells (EGFR+/HER2++) showed sensitivity to EGFR-specific inhibition. Interestingly, resistance of LN-18 to EGFR inhibition was overcome by AEE788 treatment, supposedly due to its additional HER2 inhibition. Application of AEE788 resulted in blockage of EGF-dependent EGFR/HER2-heterodimer activation in LN-18 cells, disclosing a possible mediating mechanism for overcoming EGFR-resistance. TKI treatment resulted in significant blockage of both Akt and MAPK signalling pathways, but an incomplete inhibition of PI3K/Akt paralleled the resistance of cells to TKI-induced growth inhibition. Furthermore, the bispecific EGFR/HER2 inhibitor AEE788 showed a radio-sensitising effect in EGFR-overexpressing cells. Taken together, we conclude that inhibition of HER2 in EGFR-overexpressing tumours may harbour the potential to overcome resistance to EGFR-targeted therapy and exert radio-sensitising properties. We suggest that responsiveness to EGFR targeted therapy is mediated through impairment of EGFR/ HER2 heterodimer signalling, and thus depends on the ratio of EGFR to HER2 rather than on the amount of individual receptors.
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PMID:Effect of additional inhibition of human epidermal growth factor receptor 2 with the bispecific tyrosine kinase inhibitor AEE788 on the resistance to specific EGFR inhibition in glioma cells. 2087 94

Cutaneous squamous cell carcinoma (SCC) ranks second in the frequency of all skin tumors. Its incidence has risen significantly due to an increased sun exposure and the number of immunocompromised patients. It has a well-defined progression with known precursor lesions called actinic keratosis. The degree of cellular differentiation, tumor thickness, location, and other features has prognostic value. It has a better prognosis than mucosal SCC of the head and neck, also called head and neck squamous cell carcinoma (HNSCC). Ultraviolet light plays a fundamental role as an initiator and promoter of carcinogenesis of SCC, allowing the accumulation of genetic alterations that allows a selective growth advantage. The TP53 (p53) gene often mutates and Ras is frequently activated, but with low frequency of mutations. Normally, the extracellular signals determine whether the cells move from a quiescent state into an active proliferative state. In tumor cells an increase in the production of growth factors and its receptors can be often seen that gives rise to such an autocrine circuit facilitating cellular division. Recently, frequent mutations in the epidermal growth factor receptor (EGFR) have been detected in lung cancer, mainly deletions in exon 19 and L858R mutation in exon 21. These are located at the EGFR tyrosine kinase domain (TK). EGFR TK mutations produce activation of the signaling pathways downstream and preferentially activated antiapoptotic pathways (PI3K/AKT, JAK-STAT and ERK/MAPK). These mutations are correlated with the clinical response of patients to tyrosine kinase inhibitors (gefinitib and erlotinib), because the tumor cells are addicted to the constant activation of specific signaling pathways. Glioblastoma shows another EGFR mutation (EGFRvIII), corresponding to a deletion of the extracellular domain, and it is present in 24-67% of these tumors. This variant has been found in 42% of HNSCC, related to the poor response to monoclonal antibody cetuximab. Many observations show that there are abnormalities in the expression of epidermal growth factor receptor (EGFR) and/or its ligands in HNSCC with frequent activation of multiple pathways downstream EGFR, and unrelated to RAS mutation. This suggests the possibility of activation by mutation or overexpression of a component of the pathway located upstream-Ras. While in other tumors, especially lung cancer and glioblastoma, the EGFR mutations are frequent genetic events, it is unknown whether EGFR is mutated or amplified in SCC of the skin and what would be its pathogenic role in this malignancy and its precursors.
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PMID:Epidermal growth factor receptor (EGFR) and squamous cell carcinoma of the skin: molecular bases for EGFR-targeted therapy. 2153 Oct 84

Glioblastoma is the most common and malignant form of primary astrocytoma. Upon investigation of the insulin-like growth factor (IGF) pathway, we found the IGF2BP3/IMP3 transcript and protein to be up-regulated in GBMs but not in lower grade astrocytomas (p < 0.0001). IMP3 is an RNA binding protein known to bind to the 5'-untranslated region of IGF-2 mRNA, thereby activating its translation. Overexpression- and knockdown-based studies establish a role for IMP3 in promoting proliferation, anchorage-independent growth, invasion, and chemoresistance. IMP3 overexpressing B16F10 cells also showed increased tumor growth, angiogenesis, and metastasis, resulting in poor survival in a mouse model. Additionally, the infiltrating front, perivascular, and subpial regions in a majority of the GBMs stained positive for IMP3. Furthermore, two different murine glioma models were used to substantiate the above findings. In agreement with the translation activation functions of IMP3, we also found increased IGF-2 protein in the GBM tumor samples without a corresponding increase in its transcript levels. Also, in vitro IMP3 overexpression/knockdown modulated the IGF-2 protein levels without altering its transcript levels. Additionally, IGF-2 neutralization and supplementation studies established that the proproliferative effects of IMP3 were indeed mediated through IGF-2. Concordantly, PI3K and MAPK, the downstream effectors of IGF-2, are activated by IMP3 and are found to be essential for IMP3-induced cell proliferation. Thus, we have identified IMP3 as a GBM-specific proproliferative and proinvasive marker acting through IGF-2 resulting in the activation of oncogenic PI3K and MAPK pathways.
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PMID:Insulin growth factor-2 binding protein 3 (IGF2BP3) is a glioblastoma-specific marker that activates phosphatidylinositol 3-kinase/mitogen-activated protein kinase (PI3K/MAPK) pathways by modulating IGF-2. 2161 8

Glioblastoma is one of the most aggressive types of human cancer, with invariable and fatal recurrence even after multimodal intervention, for which cancer stem-like cells (CSLCs) are now being held responsible. Our recent findings indicated that combinational inhibition of phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (mTOR) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways effectively promotes the commitment of glioblastoma CSLCs to differentiation and thereby suppresses their tumorigenicity. However, the mechanism by which these two signaling pathways are coordinated to regulate differentiation and tumorigenicity remains unknown. Here, we identified FoxO3a, a common phosphorylation target for Akt and ERK, as a key transcription factor that integrates the signals from these pathways. Combinational blockade of both the pathways caused nuclear accumulation and activation of FoxO3a more efficiently than blockade of either alone, and promoted differentiation of glioblastoma CSLCs in a FoxO3a expression-dependent manner. Furthermore, the expression of a constitutively active FoxO3a mutant lacking phosphorylation sites for both Akt and ERK was sufficient to induce differentiation and reduce tumorigenicity of glioblastoma CSLCs. These findings suggest that FoxO3a may play a pivotal role in the control of differentiation and tumorigenicity of glioblastoma CSLCs by the PI3K/Akt/mTOR and MEK/ERK signaling pathways, and also imply that developing methods targeting effective FoxO3a activation could be a potential approach to the treatment of glioblastoma.
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PMID:FoxO3a functions as a key integrator of cellular signals that control glioblastoma stem-like cell differentiation and tumorigenicity. 2179 7


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