Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Metformin enhances TRAIL-mediated antitumor activity of liver natural killer cells in mice

ABSTRACT: Metformin exerts antitumor activity across multiple cancers, largely attributed to anti-inflammatory effects and the AMP-activated protein kinase (AMPK)-mediated inhibition of mammalian target of rapamycin (mTOR). However, the effects of metformin on intrahepatic immunity remain poorly defined. We previously demonstrated that mTOR inhibition augments the antitumor function of liver natural killer (NK) cells by upregulating tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we investigated whether metformin modulates TRAIL expression on liver NK cells. Compared with vehicle control, metformin increased the proportion of TRAIL+ liver NK cells, enhanced the cytotoxicity of liver NK cells against TRAIL-sensitive tumor targets, and suppressed tumor growth in vivo. Mechanistically, metformin increased, by downregulating Eomes expression, the proportion of liver-resident NK cells (also known as type 1 innate lymphoid cells) which are an immature, TRAILhigh subset. Moreover, activation of the AMPK signaling axis may contribute to metformin-induced promotion of TRAIL+ liver NK cells. These findings indicate that metformin potentiates the antitumor activity of liver NK cells via TRAIL upregulation, supporting its potential repositioning as an immunomodulatory adjuvant for liver cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE317772 | GEO | 2026/01/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Metformin impairs cisplatin effects in cell size and proliferation of A549 lung cancer cells, modulating the mTOR and other metabolic pathways.

Project description:Lung cancer is the leading cause of cancer death worldwide and reports innate and acquired therapeutic resistance to cisplatin. Metformin (MET), an antidiabetic agent with potential antitumor activity, overcomes cisplatin resistance in some cancers through AMPK-dependent and independent mechanisms. MET is a potential treatment in cells with LKB1 mutation, even with the impairment of AMPK and overactivation of mTOR signaling. The present study investigated the role of mTOR signaling and other signaling pathways after MET treatment in control and resistant A549 cells, mapping pathways and possible targets for cisplatin sensitivity induced by metformin.

2021-09-09 | PXD017645 | Pride

Proteomic of huh7 grown in normal and glucose-deficient conditions

Project description:Tumor cell metabolic plasticity is essential for tumor progression and therapeutic response, but the mechanism for regulation of metabolic plasticity remain poorly explored. Here, we identify PROX1 as an essential determinant for tumor metabolic plasticity. Notably, PROX1 is significantly reduced in response to metabolic stress or AMPK activation and is elevated in LKB1-deficient tumors in mice and human. Furthermore, the Ser79 phosphorylation of PROX1 by AMPK significantly alters its protein activity and allows a rapid recruitment of CUL4-DDB1 E3 ubiquitin ligase to promote PROX1 degradation under glucose starvation, a critical event that drives BCAA metabolism rewiring to suppress mTOR signaling. Importantly, PROX1 loss or Ser79 phosphorylation in HCC shows therapeutic resistance to metformin. Consistently, genetic ablation of PROX1 renders LKB1‐deficient KRAS-driven lung cancer resistant to phenformin treatment. Conversely, mice harboring non-phosphorylated PROX1 mutant or LKB1 mutant exhibit high PROX1 stabilization, promoting liver and lung cancer progression. Clinically, AMPK-PROX1 axis in human cancers is important for patient clinical outcomes. Collectively, our results demonstrate that the deficiency in the LKB1-AMPK axis in cancers reactivates PROX1 to sustain intracellular BCAA pools, resulting in enhanced mTOR signaling, and facilitating tumorigenesis and aggressiveness.

2022-09-27 | PXD036977 | Pride

Metformin enhances TRAIL-mediated antitumor activity of liver natural killer cells in mice

Project description:Metformin enhances TRAIL-mediated antitumor activity of liver natural killer cells in mice

| PRJNA1415209 | ENA

PROX1 Orchestrates Tumor Metabolic Plasticity by Integrating LKB1-AMPK Signaling with BCAA Catabolism (ATAC-Seq)

2022-09-27 | GSE214193 | GEO

PROX1 Orchestrates Tumor Metabolic Plasticity by Integrating LKB1-AMPK Signaling with BCAA Catabolism (RNA-Seq)

2022-09-27 | GSE214192 | GEO

RNA-seq of metformin treatment in primary murine hepatocytes in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant;Tsc2-null, and Ampk-null cells

Project description:Despite being the frontline therapy for Type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill-defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB. But several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of primary hepatocytes and intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for the transcriptional response to metformin. Transcriptionally, AMPK and mTORC1 were both important for regulation of anabolic metabolism and inflammatory programs triggered by metformin treatment.

2023-08-10 | GSE157048 | GEO

RNA-seq of metformin treatment in liver in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant;Tsc2-null, and Ampk-null

Project description:Despite being the frontline therapy for Type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill-defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB. But several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for the transcriptional response to metformin. Transcriptionally, AMPK and mTORC1 were both important for regulation of anabolic metabolism and inflammatory programs triggered by metformin treatment. The hepatic transcriptional response in mice on high fat diet treated with metformin was largely ablated by AMPK-deficiency under the conditions examined, indicating the essential role of this kinase and its targets in metformin action in vivo.

2023-08-10 | GSE157049 | GEO

TYMS expression regulates AMPK-mTOR signaling in pancreatic neuroendocrine tumors

Project description:AMPK serves as a regulator of metabolic homeostasis to conserve energy in tumor cells by inhibiting ATP-anabolic processes and promoting ATP-generating pathways. When activated, AMPK reprograms cellular metabolism and imposes growth checkpoints, particularly through inhibition of the mTOR signaling pathway. Since mTOR is activated in a subset of PanNET patients, the AMPK-mTOR signaling axis is a crucial target to evaluate the risk for chemotherapy drugs resistance and overall prognosis in these patients. We now report that elevated TYMS levels downregulates AMPK signaling and activates mTOR signaling in PanNET tumor cells. These data suggest a new role for TYMS inhibition to modulate the AMPK-mTOR signaling axis and impact the efficacy of current mTOR inhibitory agents in the management of patients with advanced PanNET.

2024-11-18 | MSV000096459 | MassIVE

Ribosome profiling of metformin treatment in primary murine hepatocytes in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant;Tsc2-null, and Ampk-null cells

2023-08-10 | GSE157050 | GEO

Importance of AMPK in metformin suppression of liver glucose production

Project description:Metformin is now the most widely prescribed oral anti-diabetic agent worldwide, taken by over 150 million people annually. Although metformin has been used clinically to treat type 2 diabetes for over 60 years. Its mechanism of action remains only partially understood and controversial. In particular, this includes whether AMPK plays a role in metformin suppression of liver glucose production. To address this issue, we knocked out the AMPK catalytic alpha1 and alpha 2 subunits in the liver of HFD-fed adult homozygous mice. These mice were treated with a physiological relevent metformin dose (50 mg/kg/day) for 3 weeks. Liver samples were collected.

2019-11-13 | GSE114234 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data