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

Mnk kinases are downstream effectors of mitogen-activated protein kinase pathways and mediate phosphorylation of the eukaryotic initiation factor (eIF4E), a protein that plays a key role in the regulation of mRNA translation and is up-regulated in acute myeloid leukemia (AML). We determined the effects of chemotherapy (cytarabine) on the activation status of Mnk in AML cells and its role in the generation of antileukemic responses. A variety of experimental approaches were used, including immunoblotting, apoptosis assays, small interfering RNA (siRNA)-mediated knockdown of proteins, and clonogenic hematopoietic progenitor assays in methylcellulose. Cytarabine induced phosphorylation/activation of Mnk and Mnk-mediated phosphorylation of eIF4E on Ser209, as evidenced by studies involving pharmacological inhibition of Mnk or experiments using cells with targeted disruption of Mnk1 and Mnk2 genes. To assess the functional relevance of cytarabine-inducible engagement of Mnk/eIF4E pathway, the effects of pharmacological inhibition of Mnk on cytarabine-mediated suppression of primitive leukemic progenitors [leukemic colony forming unit (CFU-L)] were examined. Concomitant treatment of cells with a pharmacological inhibitor of Mnk or siRNA-mediated knockdown of Mnk1/2 strongly enhanced the suppressive effects of low cytarabine concentrations on CFU-L. It is noteworthy that the mammalian target of rapamycin (mTOR) inhibitor rapamycin also induced phosphorylation of eIF4E in a Mnk-dependent manner, whereas inhibition strongly enhanced its antileukemic effects. These data demonstrate that Mnk kinases are activated in a negative-feedback regulatory manner in response to chemotherapy and impair the generation of antileukemic responses. They also identify this pathway as a novel target for the design of new approaches to enhance the antileukemic effects of chemotherapy or mTOR inhibitors in AML.
 ...
PMID:Negative regulatory effects of Mnk kinases in the generation of chemotherapy-induced antileukemic responses. 2066 1

Finding an effective treatment for acute myeloid leukemia (AML) remains a challenge, and all cellular processes that are deregulated in AML cells should be considered in the design of targeted therapies. We show in our current study that the LKB1/AMPK/TSC tumor suppressor axis is functional in AML and can be activated by the biguanide molecule metformin, resulting in a specific inhibition of mammalian target of rapamycin (mTOR) catalytic activity. This induces a multisite dephosphorylation of the key translation regulator, 4E-BP1, which markedly inhibits the initiation step of mRNA translation. Consequently, metformin reduces the recruitment of mRNA molecules encoding oncogenic proteins to the polysomes, resulting in a strong antileukemic activity against primary AML cells while sparing normal hematopoiesis ex vivo and significantly reducing the growth of AML cells in nude mice. The induction of the LKB1/AMPK tumor-suppressor pathway thus represents a promising new strategy for AML therapy.
 ...
PMID:The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation. 2066 29

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling axis plays a central role in cell proliferation, growth, and survival under physiological conditions. However, aberrant PI3K/Akt/mTOR signaling has been implicated in many human cancers, including acute myelogenous leukemia (AML). Therefore, the PI3K/Akt/mTOR network is considered as a validated target for innovative cancer therapy. The limit of acceptable toxicity for standard polychemotherapy has been reached in AML. Novel therapeutic strategies are therefore needed. This review highlights how the PI3K/Akt/mTOR signaling axis is constitutively active in AML patients, where it affects survival, proliferation, and drug-resistance of leukemic cells including leukemic stem cells. Effective targeting of this pathway with small molecule kinase inhibitors, employed alone or in combination with other drugs, could result in the suppression of leukemic cell growth. Furthermore, targeting the PI3K/Akt/mTOR signaling network with small pharmacological inhibitors, employed either alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit pharmacological inhibitors of the PI3K/Akt/mTOR cascade which show efficacy and safety in the clinical setting are now underway.
 ...
PMID:The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. 2067 9

The fms-like receptor tyrosine kinase-3 (FLT3), which is important for the normal development of hematopoietic stem cells and cells of the immune system, is frequently mutated in patients with acute myeloid leukemia (AML). FLT3 is, therefore, a potential therapeutic target in AML. Recently, FLT3 inhibitors have shown therapeutic activity in AML patients with FLT3 mutations. Sorafenib and sunitinib were the first FLT3 inhibitors to be studied in the clinic and have the most clinically relevant data. Limited data are available for midostaurin (PKC412), lestaurtinib (CEP-701), tandutinib (MLN518), AC220, and KW-2449. It is likely that optimal application of these agents will involve combinations of inhibitors and combinations of inhibitors and chemotherapy, potentially with a mammalian target of rapamycin inhibitor such as everolimus or temsirolimus. This review discusses the theoretical rationale for the use of these agents and summarizes the relevant clinical data.
 ...
PMID:FLT3 inhibitors for the treatment of acute myeloid leukemia. 2073 55

We have previously shown that the plant-derived compound parthenolide (PTL) can impair the survival and leukemogenic activity of primary human acute myeloid leukemia (AML) stem cells. However, despite the activity of this agent, PTL also induces cellular protective responses that likely function to reduce its overall cytotoxicity. Thus, we sought to identify pharmacologic agents that enhance the antileukemic potential of PTL. Toward this goal, we used the gene expression signature of PTL to identify compounds that inhibit cytoprotective responses by performing chemical genomic screening of the Connectivity Map database. This screen identified compounds acting along the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways. Compared with single agent treatment, exposure of AML cells to the combination of PTL and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors significantly decreased viability of AML cells and reduced tumor burden in vitro and in murine xenotransplantation models. Taken together, our data show that rational drug combinations can be identified using chemical genomic screening strategies and that inhibition of cytoprotective functions can enhance the eradication of primary human AML cells.
 ...
PMID:Chemical genomic screening reveals synergism between parthenolide and inhibitors of the PI-3 kinase and mTOR pathways. 2118 93

Activating mutations of the FLT3 gene mediate leukemogenesis, at least in part, through activation of PI3K/AKT. The mammalian target of rapamycin (mTOR)-Raptor signaling pathway is known to act downstream of AKT. Here we show that the mTOR effectors, 4EBP1, p70S6K and rpS6, are highly activated in cultured and primary FLT3-mutated acute myeloid leukemia (AML) cells. Introduction of FLT3-ITD expressing constitutively activated FLT3 kinase further activates mTOR and its downstream effectors in BaF3 cells. We also found that mTOR signaling contributes to tumor cell survival, as demonstrated by pharmacologic inhibition of PI3K/AKT/mTOR, or total silencing of the mTOR gene. Furthermore, inhibition of FLT3 kinase results in downregulation of mTOR signaling associated with decreased survival of FLT3-mutated AML cells. These findings suggest that mTOR signaling operates downstream of activated FLT3 kinase thus contributing to tumor cell survival, and may represent a promising therapeutic target for AML patients with mutated-FLT3.
 ...
PMID:mTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells. 2106 88

Evi1 (ecotropic viral integration site 1) is essential for proliferation of hematopoietic stem cells and implicated in the development of myeloid disorders. Particularly, high Evi1 expression defines one of the largest clusters in acute myeloid leukemia and is significantly associated with extremely poor prognosis. However, mechanistic basis of Evi1-mediated leukemogenesis has not been fully elucidated. Here, we show that Evi1 directly represses phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription in the murine bone marrow, which leads to activation of AKT/mammalian target of rapamycin (mTOR) signaling. In a murine bone marrow transplantation model, Evi1 leukemia showed modestly increased sensitivity to an mTOR inhibitor rapamycin. Furthermore, we found that Evi1 binds to several polycomb group proteins and recruits polycomb repressive complexes for PTEN down-regulation, which shows a novel epigenetic mechanism of AKT/mTOR activation in leukemia. Expression analyses and ChIPassays with human samples indicate that our findings in mice models are recapitulated in human leukemic cells. Dependence of Evi1-expressing leukemic cells on AKT/mTOR signaling provides the first example of targeted therapeutic modalities that suppress the leukemogenic activity of Evi1. The PTEN/AKT/mTOR signaling pathway and the Evi1-polycomb interaction can be promising therapeutic targets for leukemia with activated Evi1.
 ...
PMID:Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins. 2128 8

Rapidly proliferating solid tumor cells are often dependent on glycolysis for ATP production even in normoxia (the Warburg effect), however it is not yet clear whether acute leukemias have a similarly increased dependence on aerobic glycolysis. We report that all acute leukemia subtypes (pre-B ALL, T-ALL and AML) demonstrated growth arrest and cell death when treated the novel glycolysis inhibitor 3-BrOP. Potentiated ATP depletion and pro-apoptotic effects were seen for 3-BrOP combinations with the cytochrome-c-reductase inhibitor antimycin A and the mTOR inhibitor rapamycin. These results reveal a potential role for glycolysis inhibition in acute leukemia subtypes and suggest potential combinations.
 ...
PMID:Targeting glycolysis in leukemia: a novel inhibitor 3-BrOP in combination with rapamycin. 2131 58

A novel strategy has been suggested to enhance rapamycin-based cancer therapy through combining mammalian target of rapamycin (mTOR)-inhibitors with an inhibitor of the phosphatydilinositol 3-kinase PI3K/Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. However, recent study demonstrated the potentiating effect of rapamycin on all-trans-retinoic acid (ATRA)-mediated differentiation of acute myelogenous leukemia (AML) cells, prompting us to investigate the effects of longitudinal inhibition of PI3K/Akt/mTOR signaling pathway on both proliferation and differentiative capacity of AML. In NB4, HL-60, U937 and K562 cell lines, rapamycin exerted minimal antiproliferative effects, and combining PI3K inhibitor LY 294002 and rapamycin inhibited proliferation more than LY 294002 alone. Rapamycin potentiated differentiation of ATRA-treated NB4 cells, but the combination of rapamycin and LY 294002 inhibited the expression of CD11b in both ATRA- and phorbol myristate acetate (PMA)-stimulated cells more than PI3K inhibitor alone. These results demonstrate that, although the combination of PI3K inhibitor and rapamycin is more effective in inhibiting proliferation of AML, the concomitant inhibition of PI3K and mTOR by LY 294002 and rapamycin has more inhibitory effects on ATRA-mediated differentiation than the presence of PI3K-inhibitor alone, and diminishes positive effects of rapamycin on leukemia cell differentiation.
 ...
PMID:Combined inhibition of PI3K and mTOR exerts synergistic antiproliferative effect, but diminishes differentiative properties of rapamycin in acute myeloid leukemia cells. 2133 64

Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
 ...
PMID:Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors. 2134 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>