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3 results on '"AKT/MAMMALIAN TARGET OF RAPAMYCIN (MTOR)"'

1. Cadmium toxicity induces ER stress and apoptosis via impairing energy homoeostasis in cardiomyocytes.

Author

Chun-yan Chen, Shao-li Zhang, Zhi-yong Liu, Yong Tian, and Qian Sun

Abstract

Cadmium, a highly toxic environmental pollutant, is reported to induce toxicity and apoptosis in multiple organs and cells, all possibly contributing to apoptosis in certain pathophysiologic situations. Previous studies have described that cadmium toxicity induces biochemical and physiological changes in the heart and finally leads to cardiac dysfunctions, such as decreasing contractile tension, rate of tension development, heart rate, coronary flow rate and atrioventricular node conductivity. Although many progresses have been made, the mechanism responsible for cadmium-induced cellular alternations and cardiac toxicity is still not fully understood. In the present study, we demonstrated that cadmium toxicity induced dramatic endoplasmic reticulum (ER) stress and impaired energy homoeostasis in cultured cardiomyocytes. Moreover, cadmium toxicity may inhibit protein kinase B (AKT)/mTOR (mammalian target of rapamycin) pathway to reduce energy productions, by either disrupting the glucose metabolism or inhibiting mitochondrial respiratory gene expressions. Our work will help to reveal a novel mechanism to clarify the role of cadmium toxicity to cardiomyocytes and provide new possibilities for the treatment of cardiovascular diseases related to cadmium toxicity. [ABSTRACT FROM AUTHOR]

Published
2015
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2. GDF15 regulates Kv2.1-mediated outward K+ current through the Akt/mTOR signalling pathway in rat cerebellar granule cells

Author

Chang-Ying Wang, An-Qi Huang, Yan-Ai Mei, and Meng-Hua Zhou

Subjects
MIC-1, macrophage inhibitory cytokine-1, MAPK/ERK pathway, Biochemistry, DMEM, Dulbecco’s modified Eagle’s medium, Rats, Sprague-Dawley, chemistry.chemical_compound, Shab Potassium Channels, IA, fast-transient outward K+ current, Cerebellum, TGFβ, transforming growth factor β, Cells, Cultured, Akt/mammalian target of rapamycin (mTOR), TOR Serine-Threonine Kinases, growth/differentiation factor 15 (GDF15), qPCR, quantitative real-time PCR, Cell biology, Oncogene Protein v-akt, DIC, days in culture, GAPDH, glyceraldehyde-3-phosphate dehydrogenase, TGFβR, TGFβ receptor, Phosphorylation, delayed-rectifier outward K+ current (IK), 4-AP, 4-aminopyridine, Signal transduction, IK, delayed-rectifier outward K+ current, PI3K, phosphoinositide 3-kinase, Signal Transduction, Research Article, Growth Differentiation Factor 15, mTOR, mammalian target of rapamycin, Protein Serine-Threonine Kinases, Biology, ERK, extracellular-signal-regulated kinase, cerebellar granule neuron (CGN), CHX, cycloheximide, GDF15, growth/differentiation factor 15, Animals, Humans, TTX, tetrodotoxin, Molecular Biology, Protein kinase B, PI3K/AKT/mTOR pathway, Kv2.1, NP40, Nonidet P40, RPTOR, Receptor, Transforming Growth Factor-beta Type II, R-Smad, receptor-regulated Smad, Tyrosine phosphorylation, Cell Biology, Rats, CGN, cerebellar granule neuron, Animals, Newborn, chemistry, MEK, MAPK/ERK kinase, PKA, protein kinase A, Receptors, Transforming Growth Factor beta, MAPK, mitogen-activated protein kinase, Transforming growth factor
Abstract

GDF15 (growth/differentiation factor 15), a novel member of the TGFβ (transforming growth factor β) superfamily, plays critical roles in the central and peripheral nervous systems, but the signal transduction pathways and receptor subtypes involved are not well understood. In the present paper, we report that GDF15 specifically increases the IK (delayed-rectifier outward K+ current) in rat CGNs (cerebellar granule neurons) in time- and concentration-dependent manners. The GDF15-induced amplification of the IK is mediated by the increased expression and reduced lysosome-dependent degradation of the Kv2.1 protein, the main α-subunit of the IK channel. Exposure of CGNs to GDF15 markedly induced the phosphorylation of ERK (extracellular-signal-regulated kinase), Akt and mTOR (mammalian target of rapamycin), but the GDF15-induced IK densities and increased expression of Kv2.1 were attenuated only by Akt and mTOR, and not ERK, inhibitors. Pharmacological inhibition of the Src-mediated phosphorylation of TGFβR2 (TGFβ receptor 2), not TGFβR1, abrogated the effect of GDF15 on IK amplification and Kv2.1 induction. Immunoprecipitation assays showed that GDF15 increased the tyrosine phosphorylation of TGFβRII in the CGN lysate. The results of the present study reveal a novel regulation of Kv2.1 by GDF15 mediated through the TGFβRII-activated Akt/mTOR pathway, which is a previously uncharacterized Smad-independent mechanism of GDF15 signalling., In the present paper, we report for the first time that GDF15 increases Kv2.1 expression through TGFβRII to activate the Akt/mTOR pathway, which reveals an unanticipated role of the non-Smad-dependent pathway in the previously uncharacterized signalling mediated by GDF15.

Published
2014
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3. Temsirolimus, an mTOR inhibitor, in combination with lower-dose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML-1107)

Author

Amadori, S, Stasi, R, Martelli, Am, Venditti, A, Meloni, G, Pane, F, Martinelli, G, Lunghi, M, Pagano, L, Cilloni, D, Rossetti, E, DI RAIMONDO, Francesco, Fozza, C, Annino, L, Chiarini, F, Ricci, F, Ammatuna, E, La Sala, E, Fazi, P, Vignetti, M., Amadori, S, Stasi, R, Martelli, Am, Venditti, A, Meloni, G, Pane, Fabrizio, Martinelli, G, Lunghi, M, Pagano, L, Cilloni, D, Rossetti, E, Di Raimondo, F, Fozza, C, Annino, L, Chiarini, F, Ricci, F, Ammatuna, E, La Sala, E, Fazi, P, Vignetti, M., Amadori S., Stasi R., Martelli A.M., Venditti A., Meloni G., Pane F., Martinelli G., Lunghi M., Pagano L., Cilloni D., Rossetti E., Di Raimondo F., Fozza C., Annino L., Chiarini F., Ricci F., Ammatuna E., La Sala E., Fazi P., and Vignetti M.

Subjects
age factors, tor serine-threonine kinases, adenine nucleotides, disease-free survival, antineoplastic combined chemotherapy protocols, acute, acute myeloid leukaemia, administration /&/ dosage/adverse effects, administration /&/ dosage/adverse effects/analogs /&/ derivatives, adverse effects/therapeutic use, aged, antagonists /&/ inhibitors, arabinonucleosides, clofarabine, drug therapy, elderly patients, female, humans, leukemia, male, mammalian target of rapamycin, methods, middle aged, myeloid, salvage therapy, sirolimus, temsirolimus, temsirolimu, ACUTE MYELOID LEUKEMIA, AKT/MAMMALIAN TARGET OF RAPAMYCIN (MTOR), Clofarabine, ELDERLY PATIENTS, Adenine Nucleotides, administration /&/ dosage/adverse effects, Age Factors, Aged, Antineoplastic Combined Chemotherapy Protocols, adverse effects/therapeutic use, Arabinonucleosides, administration /&/ dosage/adverse effects, Disease-Free Survival, Female, Humans, Leukemia, Myeloid, Acute, drug therapy, Male, Middle Aged, Salvage Therapy, methods, Sirolimus, administration /&/ dosage/adverse effects/analogs /&/ derivatives, TOR Serine-Threonine Kinases, Leukemia, Myeloid, Acute, Settore MED/15 - Malattie del Sangue
Abstract

The mammalian target of rapamycin (mTOR) signalling pathway has emerged as an important therapeutic target for acute myeloid leukaemia (AML). This study assessed the combination of temsirolimus, an mTOR inhibitor, and lower-dose clofarabine as salvage therapy in older patients with AML. Induction consisted of clofarabine 20 mg/m2 on days 15 and temsirolimus 25 mg (flat dose) on days 1, 8 and 15. Patients achieving complete remission with (CR) or without (CRi) full haematological recovery could receive monthly temsirolimus maintenance. In 53 evaluable patients, the overall remission rate (ORR) was 21% (8% CR, 13% CRi). Median disease-free survival was 3.5 months, and median overall survival was 4 months (9.1 months for responders). The most common non-haematological severe adverse events included infection (48%), febrile neutropenia (34%) and transaminitis (11%). The 30-d all-cause induction mortality was 13%. Laboratory data from 25 patients demonstrated that a >50%in vivo inhibition of S6 ribosomal protein phosphorylation was highly correlated with response rate (75% with inhibition versus 0% without inhibition; P = 0.0001), suggesting that targeting the mTOR pathway is clinically relevant. The acceptable safety profile and the predictive value of target inhibition encourage further investigation of this novel regimen.

Published
2012

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