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)

The mammalian target of rapamycin (mTOR) modulates key signaling pathways that promote uncontrolled proliferation of glioblastoma multiforme (GBM). Because rapid tumor proliferation may contribute to the clinical radioresistance of GBM tumors, the combination of rapamycin, a selective mTOR inhibitor, and radiation was studied in vitro and in vivo in a GBM model. In monolayer cultures of U87 and SKMG-3 cells, rapamycin had no impact on radiation sensitivity. In contrast, rapamycin significantly enhanced the efficacy of fractionated radiation of established U87 xenografts in nude mice. Similar effects were seen in U87 spheroids treated with rapamycin and radiation, which suggests that the sensitizing effects of this drug are dependent on disruption of mTOR signaling pathways specifically within tumor cells. Inhibition of these signaling pathways can lead to inhibition of G(1)-specific cyclin-dependent kinase activities, and this could contribute to the sensitizing effects of rapamycin. Consistent with this idea, roscovitine, a specific cyclin-dependent kinase inhibitor, also enhanced the efficacy of fractionated radiation in U87 spheroids. These data demonstrate that inhibition of tumor proliferation does not diminish the efficacy of fractionated radiation and suggest that disruption of key signal transduction pathways may significantly enhance the effectiveness of radiation therapy in malignant gliomas.
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PMID:Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. 1249 72

The mechanisms that regulate mammalian cell size during development and homeostatic maintenance are poorly understood. The tumor suppressor Pten is required for correct maintenance of mammalian neuronal soma size. Selective inactivation of Pten in postnatal granule neurons of the cerebellum and dentate gyrus in mouse causes cell-autonomous hypertrophy as well as more complex phenotypes, including progressive macrocephaly, seizures, and premature death. To determine the contribution of mTor signaling to Pten-mediated growth regulation in the mammalian nervous system, we treated Pten conditional knockout mice with CCI-779, a specific mTor inhibitor. mTor inhibition decreased the seizure frequency and death rate in Pten mutant mice, prevented the increase in Pten-deficient neuronal soma size in young mice, and reversed neuronal soma enlargement in adult mice. mTor inhibition did not decrease the size of wild-type adult neurons. Thus, mTor is required for neuronal hypertrophy downstream of Pten deficiency, but is not required for maintenance of normal neuronal soma size. mTOR inhibitors may be useful therapeutic agents for diseases in brain resulting from PTEN deficiency such as Lhermitte-Duclos disease or glioblastoma multiforme.
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PMID:mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo. 1453 28

Genetic alterations targeting the PTEN tumor suppressor gene are among the most frequently noted somatic mutations in human cancers. Such lesions have been noted in cancers of the prostate and endometrium and in glioblastoma multiforme, among many others. Moreover, germline mutation of PTEN leads to the development of the related hereditary cancer predisposition syndromes, Cowden disease, and Bannayan-Zonana syndrome, wherein breast and thyroid cancer incidence is elevated. The protein product, PTEN, is a lipid phosphatase, the enzymatic activity of which primarily serves to remove phosphate groups from key intracellular phosphoinositide signaling molecules. This activity normally serves to restrict growth and survival signals by limiting activity of the phosphoinositide-3 kinase (PI3K) pathway. Multiple lines of evidence support the notion that this function is critical to the ability of PTEN to maintain cell homeostasis. Indeed, the absence of functional PTEN in cancer cells leads to constitutive activation of downstream components of the PI3K pathway including the Akt and mTOR kinases. In model organisms, inactivation of these kinases can reverse the effects of PTEN loss. These data raise the possibility that drugs targeting these kinases, or PI3K itself, might have significant therapeutic activity in PTEN-null cancers. Akt kinase inhibitors are still in development; however, as a first test of this hypothesis, phase I and phase II trials of inhibitors of mTOR, namely, rapamycin and rapamycin analogs are underway.
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PMID:The biology and clinical relevance of the PTEN tumor suppressor pathway. 1525 63

The phosphoinositide 3-kinase (PI3-kinase) signaling pathway is frequently aberrantly activated in glioblastoma multiforme (GM) by mutation or loss of the 3' phospholipid phosphatase PTEN. PTEN abnormalities result in inappropriate signaling to downstream molecules including protein kinase B (PKB/Akt), and mammalian target of rapamycin (mTOR). PI3-kinase activation increases resistance to radiation-induced cell death; conversely, PI3-kinase inhibition enhances the sensitivity of tumors to radiation. The effects of LY294002, a biochemical inhibitor of PI3-kinase, on the response to radiation were examined in the PTEN mutant glioma cell line U251 MG. Low doses of LY294002 sensitized U251 MG to clinically relevant doses of radiation. In contrast to LY294002, rapamycin, an inhibitor of mTOR, did not result in radiosensitization. We demonstrate that among multiple known targets of LY294002, PI3-kinase is the most likely molecule responsible for LY294002-induced radiosensitization. Furthermore, using a myristoylated PKB/Akt construct, we identified PKB/Akt as the downstream molecule that mediates the synergistic cytotoxicity between LY294002 and radiation. Thus PI3-kinase dysregulation may contribute to the notable radioresistance of GM tumors and inhibition of PKB/Akt offers an excellent target to enhance radiosensitivity.
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PMID:PKB/Akt mediates radiosensitization by the signaling inhibitor LY294002 in human malignant gliomas. 1573 8

Combined activation of Ras and AKT leads to the formation of astrocytic glioblastoma multiforme (GBM) in mice. In human GBMs, AKT is not mutated but is activated in approximately 70% of these tumors, in association with loss of PTEN and/or activation of receptor tyrosine kinases. Mechanistic justification for the therapeutic blockade of targets downstream of AKT, such as mTOR, in these cancers requires demonstration that the oncogenic effect of PTEN loss is through elevated AKT activity. We demonstrate here that loss of Pten is similar to AKT activation in the context of glioma formation in mice. We further delineate the role of mTOR activity downstream of AKT in the maintenance of AKT+KRas-induced GBMs. Blockade of mTOR results in regional apoptosis in these tumors and conversion in the character of surviving tumor cells from astrocytoma to oligodendroglioma. These data suggest that mTOR activity is required for the survival of some cells within these GBMs, and mTOR appears required for the maintenance of astrocytic character in the surviving cells. Furthermore, our study provides the first example of conversion between two distinct tumor types usually thought of as belonging to specific lineages, and provides evidence for signal transduction-mediated transdifferentiation between glioma subtypes.
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PMID:mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. 1596 13

The tumor-selective, proapoptotic, death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a mediator of antitumor drug activity and in itself is a promising agent for the treatment of human malignancies. Like many tumors, however, glioblastoma multiforme (GBM), the most fatal form of glioma, exhibits a range of TRAIL sensitivity, and only a small percentage of GBM tumors undergo TRAIL-induced apoptosis. We here show that TRAIL resistance in GBM is a consequence of overexpression of the short isoform of the caspase-8 inhibitor, c-FLICE inhibitory protein (FLIP(S)), and that FLIP(S) expression is in turn translationally enhanced by activation of the Akt-mammalian target of rapamycin (mTOR)-p70 S6 kinase 1 (S6K1) pathway. Conversely, pharmacologic or genetic inhibition of mTOR, or the mTOR target S6K1, suppresses polyribosomal accumulation of FLIP(S) mRNA, FLIP(S) protein expression, and TRAIL resistance. In archived material from 12 human GBM tumors, PTEN status was a predictor of activation of the Akt-mTOR-S6K1 pathway and of FLIP(S) levels, while in xenografted human GBM, activation status of the PTEN-Akt-mTOR pathway distinguished the tumors inherently sensitive to TRAIL from those which could be sensitized by the mTOR inhibitor rapamycin. These results define the mTOR pathway as a key limiter of tumor elimination by TRAIL-mediated mechanisms, provide a means by which the TRAIL-sensitive subset of GBM can be identified, and provide rationale for the combined use of TRAIL with mTOR inhibitors in the treatment of human cancers.
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PMID:mTOR controls FLIPS translation and TRAIL sensitivity in glioblastoma multiforme cells. 1619 61

Elevated epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) signaling are known to contribute to the malignant properties of glioblastoma multiforme (GBM), which include uncontrolled cell proliferation and evasion of apoptosis. Small molecule inhibitors that target these protein kinases have been evaluated in multiple clinical trials for cancer patients, including those with GBM. Here we have examined the cellular and molecular effects of a combined kinase inhibition of mTOR (rapamycin) and EGFR (EKI-785) in U87 and U251 GBM cells. Simultaneous treatment with rapamycin and EKI-785 results in synergistic antiproliferative as well as proapoptotic effects. At a molecular level, rapamycin alone significantly decreases S6 phosphorylation, whereas EKI-785 alone promotes substantially reduced signal transducer and activator of transcription (STAT3) phosphorylation. Treatment with rapamycin alone also increases Akt phosphorylation on Ser-473, but this effect is blocked by a simultaneous administration of EKI-785. Individually, EKI-785 diminishes while rapamycin promotes the binding of the translation inhibitor eukaryotic initiation factor 4E binding protein (4EBP1) to the eukaryotic translation initiation factor 4E (eIF4E). In spite of these opposing effects, the highest level of 4EBP1-eIF4E binding occurs with the combination of the two inhibitors. These results indicate that the inhibition of EGFR and mTOR has distinct as well as common signaling consequences and provides a molecular rationale for the synergistic antitumor effects of EKI-785 and rapamycin administration.
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PMID:Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells. 1624 75

Malignant gliomas, among which glioblastomas constitute the largest group, are characterized by a dramatically diffuse infiltration into the brain parenchyma with, as a consequence, the fact that no patient with glioblastoma multiforme (GBM) has been cured to date. Migrating GBM cells are resistant to apoptosis (Type I programmed cell death), and thus to radiotherapy and conventional chemotherapy, because of the constitutive activation of several intracellular signaling pathways, of which the most important identified to date are the pathways controlled by phosphatidylinositol 3-kinase, Akt, and the mammalian target of rapamycin (mTOR). Migrating GBM cells seem to be less prone to resist autophagy (Type II programmed cell death), and disruption of the pathway controlled by mTOR induces marked autophagic processes in GBM cells. Temozolomide is the most efficacious cytotoxic drug employed today to combat glioblastoma, and this drug exerts its cytotoxic activity through proautophagic processes. Thus, autophagy represents a kind of Trojan horse that can be used to bypass, at least partly, the dramatic resistance of glioblastoma to radiotherapy and proapoptotic-related chemotherapy.
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PMID:Autophagy, the Trojan horse to combat glioblastomas. 1670 38

Glioblastoma multiforme is the most common and lethal form of primary brain cancer. Diagnosis of this advanced glioma has a poor prognosis due to the ineffectiveness of current therapies. Aberrant expression of receptor tyrosine kinases (RTK) in glioblastoma multiformes is suggestive of their role in initiation and maintenance of these tumors of the central nervous system. In fact, ectopic expression of the orphan RTK ROS is a frequent event in human brain cancers, yet the pathologic significance of this expression remains undetermined. Here, we show that a glioblastoma-associated, ligand-independent rearrangement product of ROS (FIG-ROS) cooperates with loss of the tumor suppressor gene locus Ink4a;Arf to produce glioblastomas in the mouse. We show that this FIG-ROS-mediated tumor formation in vivo parallels the activation of the tyrosine phosphatase SH2 domain-containing phosphatase-2 (SHP-2) and a phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling axis in tumors and tumor-derived cell lines. We have established a fully penetrant preclinical model for adult onset of glioblastoma multiforme in keeping with major genetic events observed in the human disease. These findings provide novel and important insights into the role of ROS and SHP-2 function in solid tumor biology and set the stage for preclinical testing of targeted therapeutic approaches.
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PMID:ROS fusion tyrosine kinase activates a SH2 domain-containing phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling axis to form glioblastoma in mice. 1688 44

The mammalian target of rapamycin (mTOR) plays a critical role in the regulation of cell growth, proliferation and survival. Components of the mTOR pathway are activated in a variety of tumors, including glioblastoma multiforme (GBM), and we have found that one surprising consequence of mTOR pathway activation is resistance of GBMs to the proapoptotic effects of agents such as APO2L/TRAIL. mTOR inhibition has become feasible following the development of rapamycin and comparable analogs with improved pharmacological properties, including CCI-779, RAD001 and AP23573. Numerous studies have also demonstrated promising proapoptotic activity, with relatively mild side effects, using rapamycin analogs in vitro and in vivo in conjunction with APO2L/TRAIL. These studies suggest that mTOR inhibitors can be combined with APO2L/TRAIL as a potential tumor-selective therapy.
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PMID:Use of APO2L/TRAIL with mTOR inhibitors in the treatment of glioblastoma multiforme. 1702 Apr 63


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