scholarly journals Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

2020 ◽  
Vol 21 (14) ◽  
pp. 5165 ◽  
Author(s):  
Mara Bonelli ◽  
Rita Terenziani ◽  
Silvia Zoppi ◽  
Claudia Fumarola ◽  
Silvia La Monica ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Glucose Uptake ◽  
Asbestos Exposure ◽  
Metabolic Stress ◽  
Mtor Inhibitors ◽  
Mtor Signaling ◽  
Metabolic Effects ◽  
Hypoxic Conditions ◽  
Cell Energy ◽  
Dual Blockade

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6 inhibitor palbociclib in combination with PI3K/mTOR inhibitors. Here, we investigated whether such combination may have an impact on cell energy metabolism. Methods: The study was performed in MPM cells of different histotypes; metabolic analyses were conducted by measuring GLUT-1 expression and glucose uptake/consumption, and by SeaHorse technologies. Results: MPM cell models differed for their ability to adapt to metabolic stress conditions, such as glucose starvation and hypoxia. Independently of these differences, combined treatments with palbociclib and PI3K/mTOR inhibitors inhibited cell proliferation more efficaciously than single agents. The drugs alone reduced glucose uptake/consumption as well as glycolysis, and their combination further enhanced these effects under both normoxic and hypoxic conditions. Moreover, the drug combinations significantly impaired mitochondrial respiration as compared with individual treatments. These metabolic effects were mediated by the concomitant inhibition of Rb/E2F/c-myc and PI3K/AKT/mTOR signaling. Conclusions: Dual blockade of glycolysis and respiration contributes to the anti-tumor efficacy of palbociclib-PI3K/mTOR inhibitors combination.

scholarly journals Regulatory Mechanism of mTOR Signaling Pathway on Cell Energy Metabolism

2015 ◽  
Vol 45 (11) ◽  
pp. 1124-1131
Author(s):  
BiE TAN ◽  
FangYuan SHAO ◽  
YuLong YIN ◽  
Hao XIAO ◽  
MiaoMiao WU
Keyword(s):  
Energy Metabolism ◽  
Signaling Pathway ◽  
Regulatory Mechanism ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Cell Energy ◽  
Cell Energy Metabolism

scholarly journals Disruption of the HER3-PI3K-mTOR oncogenic signaling axis and PD-1 blockade as a multimodal precision immunotherapy in head and neck cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhiyong Wang ◽  
Yusuke Goto ◽  
Michael M. Allevato ◽  
Victoria H. Wu ◽  
Robert Saddawi-Konefka ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Head And Neck ◽  
Mtor Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Mtor Signaling ◽  
Wild Type ◽  
Oncogenic Signaling ◽  
Signaling Axis ◽  
Oncogenic Driver ◽  
Cancer Remission

AbstractImmune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but <20% of patients achieve durable responses. Persistent activation of the PI3K/AKT/mTOR signaling circuitry represents a key oncogenic driver in HNSCC; however, the potential immunosuppressive effects of PI3K/AKT/mTOR inhibitors may limit the benefit of their combination with ICB. Here we employ an unbiased kinome-wide siRNA screen to reveal that HER3, is essential for the proliferation of most HNSCC cells that do not harbor PIK3CA mutations. Indeed, we find that persistent tyrosine phosphorylation of HER3 and PI3K recruitment underlies aberrant PI3K/AKT/mTOR signaling in PIK3CA wild type HNSCCs. Remarkably, antibody-mediated HER3 blockade exerts a potent anti-tumor effect by suppressing HER3-PI3K-AKT-mTOR oncogenic signaling and concomitantly reversing the immune suppressive tumor microenvironment. Ultimately, we show that HER3 inhibition and PD-1 blockade may provide a multimodal precision immunotherapeutic approach for PIK3CA wild type HNSCC, aimed at achieving durable cancer remission.

scholarly journals Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2809
Author(s):  
Paolo Uva ◽  
Maria Carla Bosco ◽  
Alessandra Eva ◽  
Massimo Conte ◽  
Alberto Garaventa ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Drug Repurposing ◽  
Enrichment Analysis ◽  
Mtor Inhibitors ◽  
Gene Set Enrichment Analysis ◽  
Low Oxygen ◽  
Connectivity Map ◽  
Hypoxic Conditions ◽  
Connectivity Score

Neuroblastoma (NB) is one of the deadliest pediatric cancers, accounting for 15% of deaths in childhood. Hypoxia is a condition of low oxygen tension occurring in solid tumors and has an unfavorable prognostic factor for NB. In the present study, we aimed to identify novel promising drugs for NB treatment. Connectivity Map (CMap), an online resource for drug repurposing, was used to identify connections between hypoxia-modulated genes in NB tumors and compounds. Two sets of 34 and 21 genes up- and down-regulated between hypoxic and normoxic primary NB tumors, respectively, were analyzed with CMap. The analysis reported a significant negative connectivity score across nine cell lines for 19 compounds mainly belonging to the class of PI3K/Akt/mTOR inhibitors. The gene expression profiles of NB cells cultured under hypoxic conditions and treated with the mTORC complex inhibitor PP242, referred to as the Mohlin dataset, was used to validate the CMap findings. A heat map representation of hypoxia-modulated genes in the Mohlin dataset and the gene set enrichment analysis (GSEA) showed an opposite regulation of these genes in the set of NB cells treated with the mTORC inhibitor PP242. In conclusion, our analysis identified inhibitors of the PI3K/Akt/mTOR signaling pathway as novel candidate compounds to treat NB patients with hypoxic tumors and a poor prognosis.

scholarly journals Cyclic mechanical stretch promotes energy metabolism in osteoblast-like cells through an mTOR signaling-associated mechanism

2015 ◽  
Vol 36 (4) ◽  
pp. 947-956 ◽  
Author(s):  
ZHAOBIN ZENG ◽  
DA JING ◽  
XIAODONG ZHANG ◽  
YINZHONG DUAN ◽  
FENG XUE
Keyword(s):  
Energy Metabolism ◽  
Mechanical Stretch ◽  
Mtor Signaling

Metabolic Effects of Acute Hyperketonaemia in Man before and during An Hyperinsulinaemic Euglycaemic Clamp

1994 ◽  
Vol 86 (6) ◽  
pp. 677-687 ◽  
Author(s):  
J. Webber ◽  
E. Simpson ◽  
H. Parkin ◽  
I. A. MacDonald
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Glucose Oxidation ◽  
Respiratory Exchange Ratio ◽  
Saline Infusion ◽  
Metabolic Effects ◽  
Whole Body ◽  
Glucose Storage ◽  
Adipose Tissue Lipolysis ◽  
Subcutaneous Abdominal Adipose Tissue

1. The effects of acutely raising blood ketone body levels to those seen after 72 h of starvation were examined in 10 subjects after an overnight fast. Metabolic rate and respiratory exchange ratio were measured with indirect calorimetry before and during an insulin—glucose clamp. Arteriovenous differences were measured across forearm and subcutaneous abdominal adipose tissue. 2. In response to the clamp the respiratory exchange ratio rose from 0.82 to 0.83 during 3-hydroxybutyrate infusion and from 0.83 to 0.94 during control (saline) infusion (P < 0.001). 3. Forearm glucose uptake at the end of the clamp was 4.02 ± 0.95 (3-hydroxybutyrate infusion) and 7.09 ± 1.24 mmol min−1 100 ml−1 forearm (saline infusion). Whole body glucose uptake at the end of the clamp was 72.8 ± 7.9 (3-hydroxybutyrate infusion) and 51.0 ± 3.0 (saline infusion) mmol min−1 kg−1 body weight−1. 4. 3-Hydroxybutyrate infusion reduced the baseline abdominal venous—arterialized venous glycerol difference from 84 ± 28 to 25 ± 12 mmol/l and the non-esterified fatty acid difference from 0.60 ± 0.17 to 0.02 ± 0.09 mmol/l (P < 0.05 versus saline infusion). 5. Hyperketonaemia reduces adipose tissue lipolysis and decreases insulin-mediated forearm glucose uptake. Hyperketonaemia appears to prevent insulin-stimulated glucose oxidation, but does not reduce insulin-mediated glucose storage.

scholarly journals The lipid metabolism gene FTO influences breast cancer cell energy metabolism via the PI3K/AKT signaling pathway

2017 ◽  
Vol 13 (6) ◽  
pp. 4685-4690 ◽  
Author(s):  
Yazhuo Liu ◽  
Ruoyu Wang ◽  
Lichuan Zhang ◽  
Jianhua Li ◽  
Keli Lou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lipid Metabolism ◽  
Energy Metabolism ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Cell Energy ◽  
Lipid Metabolism Gene ◽  
Metabolism Gene

ALY688 elicits adiponectin-mimetic signaling and improves insulin action in skeletal muscle cells

2021 ◽  
Author(s):  
Hye Kyoung Sung ◽  
Patricia L. Mitchell ◽  
Sean Gross ◽  
Andre Marette ◽  
Gary Sweeney
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Muscle Cells ◽  
Temporal Analysis ◽  
Skeletal Muscle Cells ◽  
Adiponectin Receptor ◽  
Metabolic Effects

Adiponectin is well established to mediate many beneficial metabolic effects, and this has stimulated great interest in development and validation of adiponectin receptor agonists as pharmaceutical tools. This study investigated the effects of ALY688, a peptide-based adiponectin receptor agonist, in rat L6 skeletal muscle cells. ALY688 significantly increased phosphorylation of several adiponectin downstream effectors, including AMPK, ACC and p38MAPK, assessed by immunoblotting and immunofluorescence microscopy. Temporal analysis using cells expressing an Akt biosensor demonstrated that ALY688 enhanced insulin sensitivity. This effect was associated with increased insulin-stimulated Akt and IRS-1 phosphorylation. The functional metabolic significance of these signaling effects was examined by measuring glucose uptake in myoblasts stably overexpressing the glucose transporter GLUT4. ALY688 treatment both increased glucose uptake itself and enhanced insulin-stimulated glucose uptake. In the model of high glucose/high insulin (HGHI)-induced insulin resistant cells, both temporal studies using the Akt biosensor as well as immunoblotting assessing Akt and IRS-1 phosphorylation indicated that ALY688 significantly reduced insulin resistance. Importantly, we observed that ALY688 administration to high-fat high sucrose fed mice also improve glucose handling, validating its efficacy in vivo. In summary, these data indicate that ALY688 activates adiponectin signaling pathways in skeletal muscle, leading to improved insulin sensitivity and beneficial metabolic effects.

scholarly journals MondoA-Mlx Transcriptional Activity Is Limited by mTOR-MondoA Interaction

2014 ◽  
Vol 35 (1) ◽  
pp. 101-110 ◽  
Author(s):  
Mohan R. Kaadige ◽  
Jingye Yang ◽  
Blake R. Wilde ◽  
Donald E. Ayer
Keyword(s):  
Glucose Uptake ◽  
Leucine Zipper ◽  
Aerobic Glycolysis ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Nutrient Status ◽  
Regulatory Relationship ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Helix Loop Helix

Mammalian target of rapamycin (mTOR) integrates multiple signals, including nutrient status, growth factor availability, and stress, to regulate cellular and organismal growth. How mTOR regulates transcriptional programs in response to these diverse stimuli is poorly understood. MondoA and its obligate transcription partner Mlx are basic helix-loop-helix leucine zipper (bHLHZip) transcription factors that sense and execute a glucose-responsive transcriptional program. MondoA-Mlx complexes activate expression of thioredoxin-interacting protein (TXNIP), which is a potent inhibitor of cellular glucose uptake and aerobic glycolysis. Both mTOR and MondoA are central regulators of glucose metabolism, yet whether they interact physically or functionally is unknown. We show that inhibition of mTOR induces MondoA-dependent expression of TXNIP, coinciding with reduced glucose uptake. Mechanistically, mTOR binds to MondoA in the cytoplasm and prevents MondoA-Mlx complex formation, restricting MondoA's nuclear entry and reducing TXNIP expression. Further, we show that mTOR inhibitors and reactive oxygen species (ROS) regulate interaction between MondoA and mTOR in an opposing manner. Like mTOR's suppression of the MondoA-TXNIP axis, MondoA can also suppress mTOR complex 1 (mTORC1) activity via its direct transcriptional regulation of TXNIP. Collectively, these studies reveal a regulatory relationship between mTOR and the MondoA-TXNIP axis that we propose contributes to glucose homeostasis.

Sign in / Sign up

Export Citation Format

Share Document