Search results for "MTOR"

ENDOCRINE SIDE EFFECTS OF ANTI-CANCER DRUGS: Effects of anti-cancer targeted therapies on lipid and glucose metabolism

2014

During the past years, targeted therapies for cancer have been developed using drugs that have significant metabolic consequences. Among them, the mammalian target of rapamycin (mTOR) inhibitors and, to a much lesser extent, the tyrosine kinase inhibitors (TKIs) are involved. mTOR plays a key role in the regulation of cell growth as well as lipid and glucose metabolism. Treatment with mTOR inhibitors is associated with a significant increase in plasma triglycerides and LDL cholesterol. mTOR inhibitors seem to increase plasma triglycerides by reducing the activity of the lipoprotein lipase which is in charge of the catabolism of triglyceride-rich lipoproteins. The increase in LDL cholesterol…

336P PI3K pathway biomarkers and clinical response in a phase I/Ib study of GDC-0077 in hormone receptor-positive/HER2-negative breast cancer (HR+/HE…

2020

Incidence of oncogenes in PI3K/AKT and MAPK signaling pathways in breast cancer

2015

Rapamycin stimulates arginine influx through CAT2 transporters in human endothelial cells

2007

In endothelial cells Tumor Necrosis Factor-alpha (TNFalpha) stimulates arginine transport through the increased expression of SLC7A2/CAT2 transcripts. Here we show that also rapamycin, an inhibitor of mTOR kinase, stimulates system y(+)-mediated arginine uptake in human endothelial cells derived from either saphenous (HSVECs) or umbilical veins (HUVECs). When used together with TNFalpha, rapamycin produces an additive stimulation of arginine transport in both cell models. These effects are observed also upon incubation with AICAR, a stimulator of Adenosine-Monophosphate-dependent-Protein Kinase (AMPK) that produces a rapamycin-independent inhibition of the mTOR pathway. Rapamycin increases …

Quercetin ameliorates dysregulation of lipid metabolism genes via the PI3K/AKT pathway in a diet-induced mouse model of nonalcoholic fatty liver dise…

2015

Scope Flavonoids and related compounds seem to have favorable effects on nonalcoholic fatty liver disease (NAFLD) progression, although the exact mechanisms implicated are poorly understood. In this study, we aimed to investigate the effect of the flanovol quercetin on gene expression deregulation involved in the development of NAFLD, as well as the possible implication of phosphatidylinositol 3-kinase (PI3K)/AKT pathway modulation. Methods and results We used an in vivo model based on methionine- and choline-deficient (MCD) diet-fed mice and an in vitro model consisting of Huh7 cells incubated with MCD medium. MCD-fed mice showed classical pathophysiological characteristics of nonalcoholic…

A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes.

2018

Molecular checkpoints that trigger the onset of islet autoimmunity or progression to human type 1 diabetes (T1D) are incompletely understood. Using T cells from children at an early stage of islet autoimmunity without clinical T1D, we find that a microRNA181a (miRNA181a)-mediated increase in signal strength of stimulation and costimulation links nuclear factor of activated T cells 5 (NFAT5) with impaired tolerance induction and autoimmune activation. We show that enhancing miRNA181a activity increases NFAT5 expression while inhibiting FOXP3+ regulatory T cell (Treg) induction in vitro. Accordingly, Treg induction is improved using T cells from NFAT5 knockout (NFAT5ko) animals, whereas alter…

A NOVEL APPROACH IN COLORECTAL CANCER AND DIABETES MANAGEMENT: ROLE OF METFORMIN AND RAPAMYCIN

Abstract The link between colorectal cancer (CRC), diabetes mellitus (DM) and inflammation is well established, and polytherapy, including rapamycin, has been commonly adopted. However, due to the relatively weak response of CRC to rapamycin, combination with other molecules including metformin has become a potentially promising approach. This study is a novel approach that aimed at assessing the effect of a combination therapy of metformin and rapamycin on the control or prevention of colorectal cancer in diabetic animals, in presence or absence of probiotics. Fifty NOD/SCIDs male mice developed xenograft by inoculating HCT116 cells into the flank; they were equally divided into diabetics …

In the literature: June 2018

2018

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a highly active family of compounds that have changed the scenario in ovarian and human epidermal growth factor receptor 2 (HER2) non-amplified breast cancer management in the recent years. Despite impressive clinical activity, a prolonged treatment with PARPi is frequently associated with acquired resistance to this therapy. The identification of mechanisms and strategies to overcome resistance are crucial. Bromodomain containing 4 (BRD4) is a member of the bromodomain and extraterminal (BET) protein family that facilitates oncogenic transcription. BRD4 is frequently amplified in high-grade serous ovarian cancer (HGSOC) and can be …

Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-γ1-driven activation of mTOR/p70S6-kinase pathway

2009

In chronic myeloid leukemia, activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway is crucial for survival and proliferation of leukemic cells. Essential downstream molecules involve mammalian target of rapamycin (mTOR) and S6-kinase. Here, we present a comprehensive analysis of the molecular events involved in activation of these key signaling pathways. We provide evidence for a previously unrecognized phospholipase C-gamma1 (PLC-gamma1)-controlled mechanism of mTOR/p70S6-kinase activation, which operates in parallel to the classical Akt-dependent machinery. Short-term imatinib treatment of Bcr-Abl-positive cells caused dephosphorylation of p70S6-K and S6-protein without inactivat…

Holo-APP and G-protein-mediated signaling are required for sAPPa-induced activation of the Akt survival pathway

2014

International audience; Accumulating evidence indicates that loss of physiologic amyloid precursor protein (APP) function leads to reduced neuronal plasticity, diminished synaptic signaling and enhanced susceptibility of neurons to cellular stress during brain aging. Here we investigated the neuroprotective function of the soluble APP ectodomain sAPPa (soluble APPa), which is generated by cleavage of APP by a-secretase along the non-amyloidogenic pathway. Recombinant sAPPa protected primary hippocampal neurons and SH-SY5Y neuroblastoma cells from cell death induced by trophic factor deprivation. We show that this protective effect is abrogated in neurons from APP-knockout animals and APP-de…