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)

We have shown that heightened AKT activity sensitized multiple myeloma cells to the antitumor effects of the mammalian target of rapamycin inhibitor CCI-779. To test the mechanism of the AKT regulatory role, we stably transfected U266 multiple myeloma cell lines with an activated AKT allele or empty vector. The AKT-transfected cells were more sensitive to cytostasis induced in vitro by rapamycin or in vivo by its analogue, CCI-779, whereas cells with quiescent AKT were resistant. The ability of mammalian target of rapamycin inhibitors to down-regulate D-cyclin expression was significantly greater in AKT-transfected multiple myeloma cells due, in part, to the ability of AKT to curtail cap-independent translation and internal ribosome entry site (IRES) activity of D-cyclin transcripts. Similar AKT-dependent regulation of rapamycin responsiveness was shown in a second myeloma model: the PTEN-null OPM-2 cell line transfected with wild-type PTEN. Because extracellular signal-regulated kinase (ERK)/p38 activity facilitates IRES-mediated translation of some transcripts, we investigated ERK/p38 as regulators of AKT-dependent effects on rapamycin sensitivity. AKT-transfected U266 cells showed significantly decreased ERK and p38 activity. However, only an ERK inhibitor prevented D-cyclin IRES activity in resistant "low-AKT" myeloma cells. Furthermore, the ERK inhibitor successfully sensitized myeloma cells to rapamycin in terms of down-regulated D-cyclin protein expression and G1 arrest. However, ectopic overexpression of an activated MEK gene did not increase cap-independent translation of D-cyclin in "high-AKT" myeloma cells, indicating that mitogen-activated protein kinase/ERK kinase/ERK activity was required, but not sufficient, for activation of the IRES. These data support a scenario where heightened AKT activity down-regulates D-cyclin IRES function in multiple myeloma cells and ERK facilitates activity.
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PMID:Regulation of D-cyclin translation inhibition in myeloma cells treated with mammalian target of rapamycin inhibitors: rationale for combined treatment with extracellular signal-regulated kinase inhibitors and rapamycin. 1913 16

Despite advances in the treatment of acute lymphoblastic leukemia (ALL), the majority of children who relapse still die of ALL. Therefore, the development of more potent but less toxic drugs for the treatment of ALL is imperative. We investigated the effects of the mammalian target of rapamycin inhibitor, RAD001 (Everolimus), in a nonobese diabetic/severe combined immunodeficiency model of human childhood B-cell progenitor ALL. RAD001 treatment of established disease increased the median survival of mice from 21.3 days to 42.3 days (P < .02). RAD001 together with vincristine significantly increased survival compared with either treatment alone (P < .02). RAD001 induced a cell-cycle arrest in the G(0/1) phase with associated dephosphorylation of the retinoblastoma protein, and reduced levels of cyclin-dependent kinases 4 and 6. Ultrastructure analysis demonstrated the presence of autophagy and limited apoptosis in cells of RAD001-treated animals. In contrast, cleaved poly(ADP-ribose) polymerase suggested apoptosis in cells from animals treated with vincristine or the combination of RAD001 and vincristine, but not in those receiving RAD001 alone. In conclusion, we have demonstrated activity of RAD001 in an in vivo leukemia model supporting further clinical development of target of rapamycin inhibitors for the treatment of patients with ALL.
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PMID:Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia. 1919 56

Galectins have the potential to provide a promising alternative for unveiling the complexity of embryonic stem (ES) cell self-renewal, although the mechanism by which galectins maintain ES cell self-renewal has yet to be identified. Galectin-1 increased [(3)H]-thymidine incorporation as well as cyclin expression and decreased p27(kip1) expression. Src and caveolin-1 phosphorylation was increased by galectin-1, and phospho-caveolin-1 was inhibited by PP2. In addition, inhibition of caveolin-1 by small interfering RNA and methyl-beta-cyclodextrin (Mbeta-CD) decreased galectin-1-induced cyclin expression and [(3)H]-thymidine incorporation. Galectin-1 caused Akt and mTOR phosphorylation, which is involved in cyclin expression. Galectin-1-induced phospho-Akt and -mTOR was inhibited by PP2, ERas siRNA, caveolin-1 siRNA and Mbeta-CD. Furthermore, mTOR phosphorylation was decreased by LY294002 and Akt inhibitor. Galectin-1-induced increase in cyclin expression and decrease in p27(kip1) was blocked by Akt inhibitor and rapamycin. In conclusion, galectin-1 increased DNA synthesis in mouse ES cells via Src, caveolin-1 Akt, and mTOR signaling pathways.
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PMID:Interaction of galectin-1 with caveolae induces mouse embryonic stem cell proliferation through the Src, ERas, Akt and mTOR signaling pathways. 1926 63

The antiproliferative properties of a group of 13 structurally diverse gold(III) compounds, including six mononuclear gold(III) complexes, five dinuclear oxo-bridged gold(III) complexes, and two organogold(III) compounds, toward several human tumor cell lines were evaluated in vitro using a systematic screening strategy. Initially all compounds were tested against a panel of 12 human tumor cell lines, and the best performers were tested against a larger 36-cell-line panel. Very pronounced antiproliferative properties were highlighted in most cases, with cytotoxic potencies commonly falling in the low micromolar--and even nanomolar--range. Overall, good-to-excellent tumor selectivity was established for at least seven compounds, making them particularly attractive for further pharmacological evaluation. Compare analysis suggested that the observed antiproliferative effects are caused by a variety of molecular mechanisms, in most cases "DNA-independent," and completely different from those of platinum drugs. Remarkably, some new biomolecular systems such as histone deacetylase, protein kinase C/staurosporine, mammalian target of rapamycin/rapamycin, and cyclin-dependent kinases were proposed for the first time as likely biochemical targets for the gold(III) species investigated. The results conclusively qualify gold(III) compounds as a promising class of cytotoxic agents, of outstanding interest for cancer treatment, while providing initial insight into their modes of action.
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PMID:Chemistry, antiproliferative properties, tumor selectivity, and molecular mechanisms of novel gold(III) compounds for cancer treatment: a systematic study. 1954 22

p70S6K/p85S6K and cdc2/cdk1 are members of the serine/threonine protein kinase family. p70S6K/p85S6K is one of the downstream effectors of the PI3K/Akt/mTOR signal transduction pathway. It phosphorylates S6 protein of 40S ribosomal subunit and thus functions in protein synthesis and cell growth. cdc2/cdk1 is a cyclin-dependent protein kinase that controls the cell cycle entry from G2 to M phase. Overexpression of phospho-p70S6K and cdc2/cdk1 has recently been identified in the majority of diffuse large B-cell lymphoma (DLBCL) specimens. Combination of small molecules that target phosphorylation of p70S6K and cdc2/cdk1 synergistically induced cell apoptosis and cell cycle G1 and G2 arrest, suggesting that they are potential molecular targets for DLBCL therapy. This review will summarize recent advances in the study of phospho-p70S6K and cdc2/cdk1 as molecular markers and therapeutic targets for DLBCL. We propose that multilevel inhibition of the PI3K/Akt/mTOR pathway and double brake at the G1 and G2 phases of the cell cycle progression are effective strategies in treating DLBCL that overexpress phospho-p70S6K and cdc2/cdk1.
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PMID:Phospho-p70S6K and cdc2/cdk1 as therapeutic targets for diffuse large B-cell lymphoma. 1961 61

The transcription factor Forkhead Box P3 (Foxp3) has been shown to play important roles in the occurring of regulatory T cells (Tregs). Limited evidence indicated that it was also expressed in tissues other than thymus and spleen, while, very recently, it was identified as a suppressor gene in breast cancer. However, the precise role and molecular mechanism of the action of Foxp3 in ovarian cancer remained unclear. To elucidate the function of Foxp3, we examined the expression of Foxp3 in ovarian cancerous cells and the consequences of up-regulation of Foxp3 in epithelial ovarian cancer cell lines, respectively. By multiple cellular and molecular approaches such as gene transfection, CCK-8 assay, flow cytometry, RT-PCR, in-cell western, wound healing assay, and invasion assay, we found that Foxp3 was weakly/no expressed in ovarian cancerous cells. Up-regulation of Foxp3 inhibited cell proliferation, decreased cell migration, and reduced cell invasion. Compared with control, Foxp3 up-regulated cells showed decreased expression of Ki-67 and cyclin-dependent kinases (CDKs). Moreover, up-regulation of Foxp3 reduced the expression of matrix metalloproteinase-2 (MMP-2) and urokinase-type plasminogen activator (uPA), resulting in the inhibition of cell migration and invasion. In addition, Foxp3 up-regulation inhibited the activation of mammalian target of rapamycin (mTOR) and NF-kappaB signaling. These findings suggested that up-regulation of Foxp3 could be a novel approach for inhibiting ovarian cancer progression.
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PMID:Up-regulation of Foxp3 inhibits cell proliferation, migration and invasion in epithelial ovarian cancer. 1962 30

Soft-tissue sarcomas (STSs) are a heterogeneous group of rare malignant tumors predominantly arising from the embryonic mesoderm. The mainstay of curative therapy is the complete surgical resection of all tumor manifestations with negative histological margins. However, up to 50% of patients will develop distant metastases during the course of their disease. The prognosis for those patients is grim with a 5-year overall survival of less than 10%. First-line systemic therapy with ifosfamide and doxorubicin results in overall response rates of only 20% by conventional response evaluation criteria in solid tumors (RECIST). However, stabilization of disease can be seen in a greater proportion. Therefore, the role of the RECIST criteria has been questioned and the implementation of new imaging studies (e.g., FDG-PET) has shown promising results in assessing early tumor response to therapy. Furthermore, a broader insight into the molecular pathways of sarcomagenesis has been gained in recent years, revealing intriguing targets for new therapeutic approaches (e.g., VEGF, VEGF receptor, IGF receptor, EGF receptor, mTOR and cyclin-dependent kinases). In addition, a growing body of evidence is linking specific genetic aberrations with clinical outcome (e.g., SYT-SXX translocation in synovial sarcoma). With further insight into the biology of STS and the combination of new treatment options with modern imaging techniques, we will most certainly be able to improve clinical outcome in patients with STS in the upcoming years.
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PMID:New medical treatment options and strategies to assess clinical outcome in soft-tissue sarcoma. 1967 Oct 35

The mammalian target of rapamycin (mTOR) pathway regulates translation of key proteins that contribute to the pathogenesis of advanced hematologic malignancies. Inhibitors of mTOR (temsirolimus, everolimus, and deforolimus) constitute a new class of antitumor agents, with potential for treatment of relapsed and/or refractory hematologic malignancies. Mantle cell lymphoma (MCL) was the first hematologic malignancy in which mTOR inhibition was explored as a treatment strategy, owing to its characteristic overexpression of cyclin D1, a G1 cyclin regulated by mTOR signaling. Temsirolimus and everolimus exhibited antitumor activity against relapsed, refractory disease in phase II studies. In a randomized phase III trial, once-weekly intravenous temsirolimus 175 mg for 3 weeks followed by 75 mg once weekly was recently shown to improve progression-free survival (p=0.0009) and objective response rate (p=0.0019) versus investigator's choice of therapy in relapsed or refractory MCL. Evidence of antitumor activity seen in early clinical trials for other non-Hodgkin lymphoma subtypes, multiple myeloma, and myeloid leukemias supports further studies of mTOR inhibitors, alone or in combination strategies, in these diseases. Overall, the clinical findings to date strengthen mTOR inhibition as a novel and promising strategy for the treatment of certain hematologic malignancies, particularly for MCL.
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PMID:Exploring mammalian target of rapamycin (mTOR) inhibition for treatment of mantle cell lymphoma and other hematologic malignancies. 1975 6

Interstitial flow in and around bone tissue is oscillatory in nature and affects the mechanical microenvironment for bone cell growth and formation. We investigated the role of oscillatory shear stress (OSS) in modulating the proliferation of human osteoblast-like MG63 cells and its underlying mechanisms. Application of OSS (0.5 +/- 4 dynes/cm(2)) to MG63 cells induced sustained activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR/p70S6K (p70S6 kinase) signaling cascades and hence cell proliferation, which was accompanied by increased expression of cyclins A and D1, cyclin-dependent protein kinases-2, -4, and -6, and bone formation-related genes (c-fos, Egr-1, and Cox-2) and decreased expression of p21(CIP1) and p27(KIP1). OSS-induced activation of PI3K/Akt/mTOR/p70S6K and cell proliferation were inhibited by specific antibodies or small interference RNAs of alpha(v)beta(3) and beta(1) integrins and by dominant-negative mutants of Shc (Shc-SH2) and focal adhesion kinase (FAK) (FAK(F397Y)). Co-immunoprecipitation assay showed that OSS induces sustained increases in association of Shc and FAK with alpha(v)beta(3) and beta(1) integrins and PI3K subunit p85, which were abolished by transfecting the cells with FAK(F397Y) or Shc-SH2. OSS also induced sustained activation of ERK, which was inhibited by the specific PI3K inhibitor LY294002 and was required for OSS-induced activation of mTOR/p70S6K and proliferation in MG63 cells. Our findings provide insights into the mechanisms by which OSS induces osteoblast-like cell proliferation through activation of alpha(v)beta(3) and beta(1) integrins and synergistic interactions of FAK and Shc with PI3K, leading to the modulation of downstream ERK and Akt/mTOR/p70S6K pathways.
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PMID:Oscillatory flow-induced proliferation of osteoblast-like cells is mediated by alphavbeta3 and beta1 integrins through synergistic interactions of focal adhesion kinase and Shc with phosphatidylinositol 3-kinase and the Akt/mTOR/p70S6K pathway. 1988 38

Although multiple myeloma (MM) remains an incurable bone marrow cancer, survival rates have dramatically improved over the past decade, most notably in the younger patient population. An understanding of MM biology and improvement in stem-cell transplantation, better supportive care, and novel therapies with higher efficacy and lower toxicity are all responsible for this improvement. Despite these trends, improvements among older patients remain modest, underscoring the need for innovative approaches. The availability of a rich pipeline of novel agents undergoing early-phase clinical trials in MM is an exciting and active area of research. Current novel agents targeting tumor and stromal compartments can be conceptualized as those that target membrane-bound receptors (insulin-like growth factor-1, vascular endothelial growth factor, CD40, etc.), intracellular signaling kinases (Janus kinase/signal transducers and activators of transcription, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin, mitogen-activated protein kinase pathways), cell cycle molecular machinery (cyclin-dependent kinases inhibitors), epigenetic abnormalities (DNA methyltransferase and histyone deacetylase), protein dynamics (heat-shock protein 90, ubiquitin-proteasome system), and tumor vasculature and microenvironment (angiogenesis, integrins). This review highlights some of these novel agents tested either alone or in combination for the treatment of MM.
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PMID:Future novel single agent and combination therapies. 2001 Jan 71


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