scholarly journals Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung

2010 ◽  
Vol 17 (4) ◽  
pp. 977-987 ◽  
Author(s):  
Luisella Righi ◽  
Marco Volante ◽  
Ida Rapa ◽  
Veronica Tavaglione ◽  
Frediano Inzani ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Differential Sensitivity ◽  
Initiation Factor ◽  
Target Of Rapamycin ◽  
Low Grade ◽  
Mtor Inhibition ◽  
Signaling Activation ◽  
Activation Status

Among alternative therapeutic strategies in clinically aggressive neuroendocrine tumors (NETs) of the lung, promising results have been obtained in experimental clinical trials with mammalian target of rapamycin (mTOR) inhibitors, though in the absence of a proven mTOR signaling activation status. This study analyzed the expression of phosphorylated mTOR (p-mTOR) and its major targets, the ribosomal p70S6-kinase (S6K) and the eukaryotic initiation factor 4E-binding protein 1 (4EBP1) in a large series of 218 surgically resected, malignant lung NETs, including 24 metastasizing typical carcinoids, 73 atypical carcinoids, 60 large cell neuroendocrine carcinomas (LCNECs), and 61 small cell carcinomas (SCLCs). By immunohistochemistry, low-to-intermediate-grade tumors as compared with high-grade tumors showed higher levels of p-mTOR and phosphorylated S6K (p-S6K) (P<0.001), at variance with phosphorylated 4EBP1 (p-4EBP1), which was mainly expressed in LCNECs and SCLCs (P<0.001). The activated status of mTOR pathway was proved by the strong correlation of p-mTOR with p-S6K and somatostatin receptor(s). Western blot analysis of NET tumor samples confirmed such findings, and differential sensitivity to mTOR inhibition according to mTOR pathway activation characteristics was determined in two lung carcinoid cell lines in vitro. None of the investigated molecules had an impact on survival. However, in low-grade tumors, low p-mTOR expression correlated with lymph node metastases (P=0.016), recurrent disease, and survival (P=0.005). In conclusion, these data demonstrate a differential mTOR activation status in the spectrum of pulmonary NETs, possibly suggesting that mTOR pathway profiling might play a predictive role in candidate patients for mTOR-targeted therapies.

scholarly journals Testosterone induces cardiomyocyte hypertrophy through mammalian target of rapamycin complex 1 pathway

2009 ◽  
Vol 202 (2) ◽  
pp. 299-307 ◽  
Author(s):  
Francisco Altamirano ◽  
César Oyarce ◽  
Patricio Silva ◽  
Marcela Toyos ◽  
Carlos Wilson ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Cardiac Cells ◽  
Initiation Factor ◽  
Target Of Rapamycin ◽  
Cardiomyocyte Hypertrophy ◽  
Akt Inhibitor ◽  
Mtor Inhibition ◽  
Akt Phosphorylation ◽  
Mtorc1 Signaling

Elevated testosterone concentrations induce cardiac hypertrophy but the molecular mechanisms are poorly understood. Anabolic properties of testosterone involve an increase in protein synthesis. The mammalian target of rapamycin complex 1 (mTORC1) pathway is a major regulator of cell growth, but the relationship between testosterone action and mTORC1 in cardiac cells remains unknown. Here, we investigated whether the hypertrophic effects of testosterone are mediated by mTORC1 signaling in cultured cardiomyocytes. Testosterone increases the phosphorylation of mTOR and its downstream targets 40S ribosomal protein S6 kinase 1 (S6K1; also known as RPS6KB1) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). The S6K1 phosphorylation induced by testosterone was blocked by rapamycin and small interfering RNA to mTOR. Moreover, the hormone increased both extracellular-regulated kinase (ERK1/2) and protein kinase B (Akt) phosphorylation. ERK1/2 inhibitor PD98059 blocked the testosterone-induced S6K1 phosphorylation, whereas Akt inhibition (Akt-inhibitor-X) had no effect. Testosterone-induced ERK1/2 and S6K1 phosphorylation increases were blocked by either 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid-acetoxymethylester or by inhibitors of inositol 1,4,5-trisphosphate (IP3) pathway: U-73122 and 2-aminoethyl diphenylborate. Finally, cardiomyocyte hypertrophy was evaluated by, the expression of β-myosin heavy chain, α-skeletal actin, cell size, and amino acid incorporation. Testosterone increased all four parameters and the increase being blocked by mTOR inhibition. Our findings suggest that testosterone activates the mTORC1/S6K1 axis through IP3/Ca2+ and MEK/ERK1/2 to induce cardiomyocyte hypertrophy.

Mammalian target of rapamycin signaling activation patterns in pancreatic neuroendocrine tumors

2013 ◽  
Vol 21 (4) ◽  
pp. 288-295 ◽  
Author(s):  
Yoko Komori ◽  
Kazuhiro Yada ◽  
Masayuki Ohta ◽  
Hiroki Uchida ◽  
Yukio Iwashita ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Pancreatic Neuroendocrine Tumors ◽  
Activation Patterns ◽  
Signaling Activation

Dose- and Schedule-Dependent Inhibition of the Mammalian Target of Rapamycin Pathway With Everolimus: A Phase I Tumor Pharmacodynamic Study in Patients With Advanced Solid Tumors

2008 ◽  
Vol 26 (10) ◽  
pp. 1603-1610 ◽  
Author(s):  
Josep Tabernero ◽  
Federico Rojo ◽  
Emiliano Calvo ◽  
Howard Burris ◽  
Ian Judson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Initiation Factor ◽  
Target Of Rapamycin ◽  
Advanced Solid Tumors ◽  
Eukaryotic Initiation Factor ◽  
Dependent Inhibition ◽  
Grade 3

PurposeEverolimus is a selective mammalian target of rapamycin (mTOR) inhibitor with promising anticancer activity. In order to identify a rationally based dose and schedule for cancer treatment, we have conducted a tumor pharmacodynamic phase I study in patients with advanced solid tumors.Patients and MethodsFifty-five patients were treated with everolimus in cohorts of 20, 50, and 70 mg weekly or 5 and 10 mg daily. Dose escalation depended on dose limiting toxicity (DLT) rate during the first 4-week period. Pre- and on-treatment steady-state tumor and skin biopsies were evaluated for total and phosphorylated (p) protein S6 kinase 1, eukaryotic initiation factor 4E (elF-4E) binding protein 1 (4E-BP1), eukaryotic initiation factor 4G (eIF-4G), AKT, and Ki-67 expression. Plasma trough levels of everolimus were determined on a weekly basis before dosing during the first 4 weeks.ResultsWe observed a dose- and schedule-dependent inhibition of the mTOR pathway with a near complete inhibition of pS6 and peIF-4G at 10 mg/d and ≥ 50 mg/wk. In addition, pAKT was upregulated in 50% of the treated tumors. In the daily schedule, there was a correlation between everolimus plasma trough concentrations and inhibition of peIF4G and p4E-BP1. There was good concordance of mTOR pathway inhibition between skin and tumor. Clinical benefit was observed in four patients including one patient with advanced colorectal cancer achieving a partial response. DLTs occurred in five patients: one patient at 10 mg/d (grade 3 stomatitis) and four patients at 70 mg/wk (two with grade 3 stomatitis, one with grade 3 neutropenia, and one with grade 3 hyperglycemia).ConclusionEverolimus achieved mTOR signaling inhibition at doses below the DLT. A dosage of 10 mg/d or 50 mg/wk is recommended for further development.

scholarly journals Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells

Blood ◽  
2008 ◽  
Vol 111 (1) ◽  
pp. 453-462 ◽  
Author(s):  
Robert Zeiser ◽  
Dennis B. Leveson-Gower ◽  
Elizabeth A. Zambricki ◽  
Neeraja Kambham ◽  
Andreas Beilhack ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Mammalian Target Of Rapamycin ◽  
Interleukin 2 ◽  
Mtor Pathway ◽  
Negative Regulator ◽  
Target Of Rapamycin ◽  
Differential Impact ◽  
Mtor Inhibition

Based on their ability to control T-cell homeostasis, Foxp3+CD4+CD25+ regulatory T cells (Tregs) are being considered for treatment of autoimmune disorders and acute graft-versus-host disease (aGVHD). When combining Tregs with the immunosuppressant rapamycin (RAPA), we observed reduced alloreactive conventional T-cell (Tconv) expansion and aGVHD lethality compared with each treatment alone. This synergistic in vivo protection was paralleled by intact expansion of polyclonal Tregs with conserved high FoxP3 expression. In contrast to Tconv, activation of Tregs with alloantigen and interleukin-2 preferentially led to signal transducer and activator of transcription 5 (STAT5) phosphorylation and not phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activity. Expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative regulator of the PI3K/Akt/mTOR pathway, remained high in Tregs but not Tconv during stimulation. Conversely, targeted deletion of PTEN increased susceptibility of Tregs to mTOR inhibition by RAPA. Differential impact of RAPA as a result of reduced usage of the mTOR pathway in Tregs compared with conventional T cells explains the synergistic effect of RAPA and Tregs in aGVHD protection, which has important implications for clinical trials using Tregs.

Mammalian target of rapamycin (mTOR) pathway signalling in lymphomas

2008 ◽  
Vol 10 ◽  
Author(s):  
Elias Drakos ◽  
George Z. Rassidakis ◽  
L. Jeffrey Medeiros
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Central Element ◽  
Mtor Inhibitors ◽  
Chemotherapeutic Agents ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
In Vivo Studies ◽  
Mtor Inhibition

AbstractThe mammalian target of rapamycin mTOR is a central element in an evolutionary conserved signalling pathway that regulates cell growth, survival and proliferation, orchestrating signals originating from growth factors, nutrients or particular stress stimuli. Two important modulators of mTOR activity are the AKT and ERK/MAPK signalling pathways. Many studies have shown that mTOR plays an important role in the biology of malignant cells, including deregulation of the cell cycle, inactivation of apoptotic machinery and resistance to chemotherapeutic agents. The development of several mTOR inhibitors, in addition to rapamycin, has facilitated studies of the role of mTOR in cancer, and verified the antitumour effect of mTOR inhibition in many types of neoplasms, including lymphomas. Clinical trials of rapamycin derivatives in lymphoma patients are already in development and there are encouraging preliminary results, such as the substantial response of a subset of mantle cell lymphoma patients to the rapamycin analogue temsirolimus. Based on results obtained from in vitro and in vivo studies of the mTOR pathway in lymphomas, it seems that better understanding of mTOR regulation will reveal aspects of lymphomagenesis and contribute to the development of more powerful, targeted therapies for lymphoma patients.

scholarly journals Dual Inhibition of Mitogen-Activated Protein Kinase Kinase and Mammalian Target of Rapamycin in Differentiated and Anaplastic Thyroid Cancer

2009 ◽  
Vol 23 (11) ◽  
pp. 1937-1937
Author(s):  
Ning Jin ◽  
Tianyun Jiang ◽  
D. Marc Rosen ◽  
Barry D. Nelkin ◽  
Douglas W. Ball
Keyword(s):  
Thyroid Cancer ◽  
Growth Inhibition ◽  
Differentiated Thyroid Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Xenograft Model ◽  
Anaplastic Thyroid Cancer ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Mtor Inhibition ◽  
Pathway Inhibition

ABSTRACT Context Differentiated thyroid cancer and anaplastic thyroid cancer tumors frequently have activation of the ras/raf /MAPK kinase (MEK)/ERK and phosphatidylinositol 3-kinase (PI-3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathways. Objective The objective of the study was to investigate the efficacy of MEK and mTOR inhibitors in preclinical thyroid cancer treatment models with defined mutation status. Experimental Design The MEK inhibitor AZD6244 (ARRY-142886) and mTOR inhibitor rapamycin were tested separately and in combination in 10 differentiated thyroid cancer and anaplastic thyroid cancer cell lines and in a xenograft model for evidence of pathway inhibition, growth inhibition, apoptosis, and long-range adaptation and resistance. Results Seven of 10 tested lines had evidence of significant basal activity of the PI-3K/AKT/mTOR pathway, with elevated phosphorylated AKT and phosphorylated p70 S6 kinase. Activation of ras/RAF/MEK/ERK was equally common in this panel. All 10 lines exhibited better than 60% growth inhibition with combined MEK and mTOR inhibition, including lines with BRAF, Ret-PTC, ras, and PTEN mutations. Rapamycin or AZD6244 alone achieved this threshold in six and two lines, respectively. Dual-pathway inhibition in the Ret-PTC mutant cell line TPC1 caused an intense G1 arrest in cell culture and reversible cytostatic inhibition in a xenograft model. We did not observe significant feedback up-regulation of AKT activation in either acute or prolonged exposures. Conclusion These preclinical results support the inclusion of thyroid cancer patients in early-phase clinical trials combining ras/RAF/MEK/ERK and PI-3K/AKT/mTOR pathway inhibition.

Targeting mammalian target of rapamycin: prospects for the treatment of inflammatory bowel diseases

2020 ◽  
Vol 27 ◽  
Author(s):  
Naser-Aldin Lashgari ◽  
Nazanin Momeni Roudsari ◽  
Saeideh Momtaz ◽  
Negar Ghanaatian ◽  
Parichehr Kohansal ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
In Vivo Studies ◽  
Cochrane Library ◽  
Mtor Signaling Pathway ◽  
Inflammatory Bowel

: Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview on plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.

scholarly journals Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)

2009 ◽  
Vol 421 (1) ◽  
pp. 29-42 ◽  
Author(s):  
Juan M. García-Martínez ◽  
Jennifer Moran ◽  
Rosemary G. Clarke ◽  
Alex Gray ◽  
Sabina C. Cosulich ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Mammalian Target Of Rapamycin ◽  
Specific Inhibitor ◽  
Initiation Factor ◽  
Target Of Rapamycin ◽  
S6 Kinase ◽  
Class 1 ◽  
Hydrophobic Motif ◽  
Ribosomal S6 Kinase

mTOR (mammalian target of rapamycin) stimulates cell growth by phosphorylating and promoting activation of AGC (protein kinase A/protein kinase G/protein kinase C) family kinases such as Akt (protein kinase B), S6K (p70 ribosomal S6 kinase) and SGK (serum and glucocorticoid protein kinase). mTORC1 (mTOR complex-1) phosphorylates the hydrophobic motif of S6K, whereas mTORC2 phosphorylates the hydrophobic motif of Akt and SGK. In the present paper we describe the small molecule Ku-0063794, which inhibits both mTORC1 and mTORC2 with an IC50 of ∼10 nM, but does not suppress the activity of 76 other protein kinases or seven lipid kinases, including Class 1 PI3Ks (phosphoinositide 3-kinases) at 1000-fold higher concentrations. Ku-0063794 is cell permeant, suppresses activation and hydrophobic motif phosphorylation of Akt, S6K and SGK, but not RSK (ribosomal S6 kinase), an AGC kinase not regulated by mTOR. Ku-0063794 also inhibited phosphorylation of the T-loop Thr308 residue of Akt phosphorylated by PDK1 (3-phosphoinositide-dependent protein kinase-1). We interpret this as implying phosphorylation of Ser473 promotes phosphorylation of Thr308 and/or induces a conformational change that protects Thr308 from dephosphorylation. In contrast, Ku-0063794 does not affect Thr308 phosphorylation in fibroblasts lacking essential mTORC2 subunits, suggesting that signalling processes have adapted to enable Thr308 phosphorylation to occur in the absence of Ser473 phosphorylation. We found that Ku-0063794 induced a much greater dephosphorylation of the mTORC1 substrate 4E-BP1 (eukaryotic initiation factor 4E-binding protein 1) than rapamycin, even in mTORC2-deficient cells, suggesting a form of mTOR distinct from mTORC1, or mTORC2 phosphorylates 4E-BP1. Ku-0063794 also suppressed cell growth and induced a G1-cell-cycle arrest. Our results indicate that Ku-0063794 will be useful in delineating the physiological roles of mTOR and may have utility in treatment of cancers in which this pathway is inappropriately activated.

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