Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ewing's sarcoma (ES) is the prototype of a family of tumors (ESFT) of neuroectodermal origin formed by small, round cells with limited neural differentiation, which arise most frequently within bones in children or adolescents. The proliferation of ESFT cells is highly dependent on the establishment of, and signaling through several growth factor-mediated autocrine loops. The mammalian target of rapamycin (mTOR) is a central regulator of translation and cell proliferation, involved in the cellular response to various nutritional, stress and mitogenic effectors. As mTOR has recently been associated with certain human cancers, we investigated the possibility that mTOR played a role in the regulation of ES cell proliferation. Results showed that ES cell lines carrying EWS/FLI-1 alleles of different types expressed different levels of total and phosphorylated mTOR protein. We demonstrate that rapamycin, an mTOR inhibitor, efficiently blocked the proliferation of all cell lines by promoting cell cycle arrest at the G1 phase. This was paralleled by the downregulation of the levels of the EWS/FLI-1 proteins, regardless of their fusion type, and the concomitant restoration of the expression of the TGF-beta type 2 receptor (TGFbeta RII), which is known to be repressed by several EWS-ETS fusion proteins. The expression of a rapamycin-resistant mTOR construct prevented both the proliferation blockade and the EWS/FLI-1 downregulation. These data demonstrate that mTOR signaling plays a central role in ES cell pathobiology and strongly suggest that the use of rapamycin as a cytostatic agent may be an efficient tool for the treatment of ES patients.
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PMID:Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 proteins and inhibits Ewing's sarcoma cell proliferation. 1468 87

Activation of NF-kappaB and autophagy are two processes involved in the regulation of cell death, but the possible cross-talk between these two signaling pathways is largely unknown. Here, we show that NF-kappaB activation mediates repression of autophagy in tumor necrosis factor-alpha (TNFalpha)-treated Ewing sarcoma cells. This repression is associated with an NF-kappaB-dependent activation of the autophagy inhibitor mTOR. In contrast, in cells lacking NF-kappaB activation, TNFalpha treatment up-regulates the expression of the autophagy-promoting protein Beclin 1 and subsequently induces the accumulation of autophagic vacuoles. Both of these responses are dependent on reactive oxygen species (ROS) production and can be mimicked in NF-kappaB-competent cells by the addition of H2O2. Small interfering RNA-mediated knockdown of beclin 1 and atg7 expression, two autophagy-related genes, reduced TNFalpha- and reactive oxygen species-induced apoptosis in cells lacking NF-kappaB activation and in NF-kappaB-competent cells, respectively. These findings demonstrate that autophagy may amplify apoptosis when associated with a death signaling pathway. They are also evidence that inhibition of autophagy is a novel mechanism of the antiapoptotic function of NF-kappaB activation. We suggest that stimulation of autophagy may be a potential way bypassing the resistance of cancer cells to anti-cancer agents that activate NF-kappaB.
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PMID:NF-kappaB activation represses tumor necrosis factor-alpha-induced autophagy. 1747 Oct 12

Recent reports on the role of the membrane-cytoskeleton linker protein ezrin in sarcomas showed an effect on the formation of metastases, dependent on the level of ezrin expression. In this study, we explore the role of ezrin in Ewing's sarcoma, a frequently fatal mesenchymal neoplasm of children and young adults. Through both immunohistochemistry and Western immunoblot studies we find ubiquitous, high-level expression of ezrin in Ewing's sarcoma. In contrast to the observations in osteosarcoma and rhabdomyosarcoma, we demonstrate that inhibition of ezrin-mediated signal transduction, through the expression of a non-phosphorylatable T567A mutant, slows primary growth of Ewing's sarcoma cells in vitro. This reduction in growth is a result of increased apoptosis in the mutant expressing cells. We further show that expression of this mutant reduces the ability of Ewing's sarcoma cells to form experimental metastases in vivo. Molecular examination reveals that the action of ezrin in Ewing's sarcoma is dependent on the AKT/mTOR signal transduction cascade, but not MAP Kinase. These results, therefore, demonstrate that, in Ewing's sarcoma, the biology of ezrin is distinct from that described in other sarcomas. This study further validates ezrin as a potential therapeutic target.
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PMID:Ezrin mediates growth and survival in Ewing's sarcoma through the AKT/mTOR, but not the MAPK, signaling pathway. 1702 19

The Ewing sarcoma family of tumors (ESFT) is one of the most common groups of malignancies arising in children, adolescents, and young adults up to approximately 25 years of age. It comprises Ewing sarcoma arising from bone and extraosseous Ewing sarcoma arising from soft tissues (which includes peripheral neuroectodermal tumors and Askin tumor arising from the chest wall). Ewing sarcoma is treated successfully in many cases by a combination of chemotherapy, surgery, and radiotherapy. A number of prognostic factors have been identified that can be used to stratify patients according to the risk of relapse, allowing optimization of treatment. These can be categorized as tumor-related factors (presence of metastases, tumor site, volume, lactic dehydrogenase level, chromosomal translocation type, presence of fusion transcripts in blood and bone marrow), treatment-related factors (local therapy, histologic response to chemotherapy, radiologic response to chemotherapy, chemotherapy regimen), and patient-related factors (gender, age). Newer chemotherapeutic agents are currently being investigated, and there is now increasing interest in the identification of molecular targets in ESFT that could be exploited therapeutically, which include the mammalian target of rapamycin (mTOR) and insulin growth factor-1 (IGF-1) receptor pathways.
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PMID:Emerging chemotherapeutic strategies and the role of treatment stratification in Ewing sarcoma. 1834 19

An early event of cell migration is characterized as the rapid reorganization of the actin cytoskeleton. Recently, we have demonstrated that rapamycin inhibits tumor cell motility. To understand the underlying mechanism, this study was set to determine whether rapamycin inhibition of cell motility is related to its prevention of F-actin reorganization. We found that rapamycin prevented type I insulin-like growth factor (IGF-I)-stimulated F-actin reorganization in human rhabdomyosarcoma (Rh30), Ewing sarcoma (Rh1), glioblastoma (U-373) and prostate carcinoma (PC-3) cells, and concurrently inhibited phosphorylation of focal adhesion proteins, including focal adhesion kinase (FAK), paxillin and p130(Cas) in the cells. The effect of rapamycin was blocked by expression of a rapamycin-resistant mutant of mTOR (mTORrr), but not a kinase-dead mTORrr. Downregulation of raptor mimicked the effect of rapamycin. Cells infected with a recombinant adenovirus expressing constitutively active and rapamycin-resistant mutant of p70 S6 kinase 1 (S6K1) conferred to resistance to rapamycin. Further, IGF-I failed to stimulate F-actin reorganization and phosphorylation of the focal adhesion proteins in the S6K1-downregulated cells. Expression of constitutively hypophosphorylated eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1-5A) inhibited IGF-I-stimulated F-actin reorganization, but did not alter the cellular protein or phosphorylation levels of the focal adhesion proteins. The results suggest that rapamycin inhibits IGF-I-induced F-actin reorganization and phosphorylation of the focal adhesion proteins by disruption of mTOR-raptor complex. Both S6K1 and 4E-BP1 pathways, mediated by the mTOR-raptor complex, are involved in the regulation of IGF-I-stimulated F-actin reorganization, but only the former controls IGF-I-stimulated phosphorylation of the focal adhesion proteins.
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PMID:Rapamycin inhibits F-actin reorganization and phosphorylation of focal adhesion proteins. 1850 40

Bone and soft tissue sarcomas are an infrequent and heterogeneous group of mesenchymal tumors, including more than a hundred different entities attending to histological patterns. Sarcomas are quite resistant to conventional chemotherapy (anthracycline and ifosfamide) with the exception of some subtypes, such as Ewing's sarcoma (ES). New drugs with proved efficacy against sarcomas include taxanes, gemcitabine, and ET-743. Preclinical studies have also identified key molecular events leading to the progression and development of sarcomas which are good candidates to targeted therapy. Inhibitors of the tyrosine kinase receptors, such as IGF-1R, c-kit, PDGFR, VEGFR, or the mTOR signaling pathway, proteasome, angiogenesis, and stress response proteins are under clinical evaluation against sarcomas. ES, a tumor characterized by chromosomal translocations that originate gene fusions (EWS-FLI1, EWS-ERG), is an example of a good chemotherapy responder tumor whose survival rate shows a plateau in recent years. Preclinical studies have identified that new targets such as HSP90 are of relevance to ES. On the other hand, recent studies showed the role of cancer stem cells (CSCs) in sarcomas and the relevance of the identification of reliable molecular markers and possible therapeutic targets. New therapeutic approaches could be directed against CSCs. This review describes more recent targeted therapy in sarcomas, with special emphasis on ES and the role of CSCs. We also emphasize the role of high throughput proteomic techniques in identifying new therapeutic targets.
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PMID:Targeting sarcomas: therapeutic targets and their rational. 1901 96

Bone sarcomas cause disproportionate morbidity and mortality and desperately need new therapies as there has been little improvement in outcomes in 20 years. Identification of critical signaling pathways, including type 1 insulin-like growth factor receptor (IGF-1R) for Ewing sarcoma and possibly osteosarcoma, and the ERBB and the Wnt signaling pathways for osteosarcoma, have emerged as receptors mediating vital signals for bone sarcoma. Akt, mammalian target of rapamycin (mTOR), phosphoinositide 3-kinases, mitogen-activated protein kinase kinase, extracellular signal-regulated kinases, and Ras pathway play key roles in at least some tumors, and inhibition of mTOR in particular will likely lead to improved survival, although clinical trials are still underway. The Notch pathway and ezrin are essential for osteosarcoma metastasis, and Fas downregulation is necessary for survival of metastases in lungs. As little is known about chondrosarcoma signaling, more preclinical work is needed. By defining vital signaling pathways in bone sarcomas, small molecule inhibitors can be applied rationally, leading to longer survival and reducing morbidity and late effects from intensive chemotherapy.
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PMID:Critical signaling pathways in bone sarcoma: candidates for therapeutic interventions. 1984 May 22

Progress in the treatment of Ewing's sarcoma, the second most common bone tumour in children and adolescents, has improved survival from about 10% in the period before chemotherapy was introduced to about 75% today for patients with localised tumours. However, patients with metastases still fare badly, and the therapy carries short-term and long-term toxicities. Multidisciplinary care is indispensable for these patients. Molecular techniques and new imaging modalities are affecting the diagnosis and classification of patients with Ewing's sarcoma. Cooperative group studies have led to chemotherapy regimens using the same drugs (vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide), although the exact regimens differ in Europe and North America. The EWS-ETS family of gene fusions and their downstream effects in Ewing's sarcomas provide opportunities for new approaches to treatment. These include the inhibition of the fusion gene or its protein product, and pathways related to IGF1 and mTOR. Inhibition of tyrosine kinases, exploitation of non-apoptotic cell death, and interference with angiogenesis are promising new approaches. With many new approaches and relatively few patients, it will be challenging to integrate new and established treatments through clinical trials.
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PMID:Ewing's sarcoma. 2015 70

Serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) has been implicated as a novel component of the mammalian target of rapamycin (mTOR) signaling pathway. Recently we have demonstrated that mTOR regulates cell motility in part through p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) pathways. Little is known about the role of PP2A in the mTOR-mediated cell motility. Here we show that rapamycin inhibited the basal or insulin-like growth factor 1 (IGF-1)-induced motility of human Ewing sarcoma (Rh1) and rhabdomyosarcoma (Rh30) cells. Treatment of the cells with rapamycin activated PP2A activity, and concurrently inhibited IGF-1 stimulated phosphorylation of Erk1/2. Inhibition of Erk1/2 with PD98059 did not significantly affect the basal mobility of the cells, but dramatically inhibited IGF-1-induced cell motility. Furthermore, inhibition of PP2A with okadaic acid significantly attenuated the inhibitory effect of rapamycin on IGF-1-stimulated phosphorylation of Erk1/2 as well as cell motility. Consistently, expression of dominant negative PP2A conferred resistance to IGF-1-stimulated phosphorylation of Erk1/2 and cell motility. Expression of constitutively active MKK1 also attenuated rapamycin inhibition of IGF-1-stimulated phosphorylation of Erk1/2 and cell motility. The results suggest that rapamycin inhibits cell motility, in part by targeting PP2A-Erk1/2 pathway.
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PMID:Rapamycin inhibits IGF-1 stimulated cell motility through PP2A pathway. 2048 67

Refractory and/or recurrent Ewing's sarcoma (EWS) remains a clinical challenge because the disease's resistance to therapy makes it difficult to achieve durable results with standard treatments that include chemotherapy, radiation, and surgery. Recently, insulin-like-growth-factor-1-receptor (IGF1R) antibodies have been shown to have a modest single-agent activity in EWS. Patient selection using biomarkers and understanding response and resistance mechanisms in relation to IGF1R and mammalian target of rapamycin pathways are areas of active research. Since EWS has a unique tumor-specific EWS-FLI1 t(11;22) translocation and oncogenic fusion protein, inhibition of EWS-FLI1 transcription, translation, and/or protein function may be key to eradicating EWS at the stem-cell level. Recently, a small molecule that blocks the protein-protein interaction of EWS-FLI1 with RNA helicase A has been shown in preclinical models to inhibit EWS growth. The successful application of this first-in-class protein-protein inhibitor in the clinic could become a model system for translocation-associated cancers such as EWS.
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PMID:Targeted Therapy of Ewing's Sarcoma. 2105 45


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