Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

13C mass isotopomer analysis (LCMS flux studies) MLL-AF9 (part III)

ABSTRACT: How cancer cells adapt to metabolically adverse conditions in patients and strive to proliferate is a fundamental question in cancer biology. Here we show that AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase, confers metabolic stress resistance to leukemia-initiating cells (LICs) and promotes leukemogenesis. Upon dietary restriction, MLL-AF9-induced murine acute myeloid leukemia (AML) activated AMPK and maintained leukemogenic potential. AMPK deletion significantly delayed leukemogenesis and depleted LICs by reducing the expression of glucose transporter 1 (Glut1), compromising glucose flux, and increasing oxidative stress and DNA damage. LICs were particularly dependent on AMPK to suppress oxidative stress in the hypoglycemic bone marrow environment. Strikingly, AMPK inhibition synergized with physiological metabolic stress caused by dietary restriction and profoundly suppressed leukemogenesis. Our results indicate that AMPK protects LICs from metabolic stress and that combining AMPK inhibition with physiological metabolic stress potently suppresses AML by inducing oxidative stress and DNA damage.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Cells

SUBMITTER: Yusuke Saitoh

PROVIDER: ST000170 | MetabolomicsWorkbench | Tue Jan 13 00:00:00 GMT 2015

REPOSITORIES: MetabolomicsWorkbench

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	mwtab	Other

Items per page:

1 - 1 of 1

Similar Datasets

13C mass isotopomer analysis (LCMS flux studies) MLL-AF9 (part II)

Project description:How cancer cells adapt to metabolically adverse conditions in patients and strive to proliferate is a fundamental question in cancer biology. Here we show that AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase, confers metabolic stress resistance to leukemia-initiating cells (LICs) and promotes leukemogenesis. Upon dietary restriction, MLL-AF9-induced murine acute myeloid leukemia (AML) activated AMPK and maintained leukemogenic potential. AMPK deletion significantly delayed leukemogenesis and depleted LICs by reducing the expression of glucose transporter 1 (Glut1), compromising glucose flux, and increasing oxidative stress and DNA damage. LICs were particularly dependent on AMPK to suppress oxidative stress in the hypoglycemic bone marrow environment. Strikingly, AMPK inhibition synergized with physiological metabolic stress caused by dietary restriction and profoundly suppressed leukemogenesis. Our results indicate that AMPK protects LICs from metabolic stress and that combining AMPK inhibition with physiological metabolic stress potently suppresses AML by inducing oxidative stress and DNA damage.

2015-01-13 | ST000157 | MetabolomicsWorkbench

13C mass isotopomer analysis (LCMS flux studies) MLL-AF9 (part I)

2015-06-12 | ST000308 | MetabolomicsWorkbench

Cardiomyocyte Specific Deletion of Sirt1 Gene Sensitizes Myocardium to Ischemia and Reperfusion Injury

Project description:A longevity gene, sirtuin 1 (SIRT1) and energy sensor AMP-activated protein kinase (AMPK) have common activators such as caloric restriction, oxidative stress and exercise.The objective is to characterize the role of cardiomyocyte SIRT1 in age-related impaired ischemic AMPK activation and increased susceptibility to ischemic insults.

2017-05-11 | GSE98749 | GEO

AMPK links acetyl-coA homeostasis to BET recruitment in acute myeloid leukemia: ChIP-seq

Project description:Altered metabolism fuels two hallmark properties of cancer cells, unlimited proliferation and differentiation blockade. AMP-activated protein kinase (AMPK) is a master regulator of bioenergetics crucial for glucose metabolism in acute myeloid leukemia (AML) and its inhibition delays leukemogenesis, but whether the metabolic function of AMPK alters AML epigenome remains unknown. Here, we demonstrate that AMPK maintains the epigenome of MLL-rearranged AML by linking acetyl-CoA homeostasis to BET bromodomain protein recruitment to chromatin. AMPK deletion reduced acetyl-CoA and histone acetylation, displacing BET proteins from chromatin in leukemia-initiating cells (LICs). In both mouse and patient-derived xenograft AML models, treating with AMPK and BET inhibitors synergistically suppressed AML. Our results provide a therapeutic rationale to target AMPK and BET for AML therapy.

2019-09-05 | GSE128000 | GEO

AMPK links acetyl-coA homeostasis to BET recruitment in acute myeloid leukemia: RNA-seq

2019-09-05 | GSE127999 | GEO

Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 (PRKAA1) knockdown effect on the transcriptome of primary human acute myeloid leukemia (AML) cells

Project description:To explore the function of AMPK signaling in acute myeloid leukemia (AML), we used shRNA to knock down the expression of PRKAA1, the catalytic subunit of the 5'-prime-AMP-activated protein kinase (AMPK), in primary human AML cells and performed RNA-seq experiment to profile transcriptional changes upon AMPK inactivation.

2018-06-01 | GSE114105 | GEO

AMPK promotes survival of c-Myc positive melanoma cells by suppressing oxidative stress

Project description:Although c-Myc is essential for melanocyte development, its role in cutaneous melanoma, the most aggressive skin cancer, is only partly understood. Here we used the NrasQ61KINK4a-/- mouse melanoma model to show that c-Myc is essential for tumor initiation, maintenance and metastasis. c-Myc expressing melanoma cells were preferentially found at metastatic sites, correlated with increased tumor aggressiveness and high tumor initiation potential. Abrogation of c-Myc caused apoptosis in primary murine and human melanoma cells. Mechanistically, c-Myc positive melanoma cells activated and became dependent on the metabolic energy sensor AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase that plays an important role in energy and redox homeostasis under stress conditions. AMPK pathway inhibition caused apoptosis of c-Myc expressing melanoma cells, while AMPK activation protected against cell death of c-Myc depleted melanoma cells through suppression of oxidative stress. Furthermore, TCGA database analysis of early stage human melanoma samples revealed an inverse correlation between c-Myc and patient survival, suggesting that c-Myc expression levels could serve as a prognostic marker for early stage disease.

2018-03-01 | GSE108447 | GEO

Pleiotropic effects of metformin on inflammation, oxidative and dicarbonyl stress in transgenic spontaneously hypertensive rats expressing human C-reactive protein.

Project description:Inflammation, oxidative and dicarbonyl stress play important roles in the pathophysiology of type 2 diabetes. Metformin is the first-line drug of choice for the treatment of type 2 diabetes because it effectively suppresses gluconeogenesis in the liver, however, its “pleiotropic“ effects remain controversial. In the current study, we tested the effects of metformin on inflammation, oxidative and dicarbonyl stress in an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP). In the SHR-CRP transgenic strain, we found that metformin treatment decreased circulating levels of inflammatory response marker IL6 while levels of human CRP remained unchanged and metformin also significantly reduced oxidative stress (levels of conjugated dienes and TBARS) in the liver while no significant effects were observed in SHR control rats. In addition, in the presence of high human CRP, metformin reduced methylglyoxal levels in left ventricles but not in kidneys. Finally, metformin treatment reduced adipose tissue lipolysis. Possible molecular mechanisms of metformin action studied by gene expression profiling in the liver revealed deregulated genes from inflammatory, insulin signaling, AMP-activated protein kinase (AMPK) signaling and gluconeogenesis pathways. It can be concluded that in the presence of high levels of human CRP metformin protects against inflammation, oxidative and dicarbonyl stress in the heart and ameliorates insulin resistance and dyslipidemia.

2016-07-03 | E-MTAB-3791 | biostudies-arrayexpress

AMPK-dependent gene expression profiles in response to small molecule AMPK activators

Project description:AMP-activated protein kinase (AMPK) is a major regulator of cellular energy homeostasis that coordinates metabolic pathways in order to balance nutrient supply with energy demand. AMPK elicits acute and diverse metabolic effects by directly phosphorylating various targets. AMPK activation also promotes metabolic reprogramming in longer term via effects on gene expression. The aim of this study is to elucidate molecular mechanism(s) by which AMPK activation modulates metabolic adaptation through its impact on gene regulation.

2019-03-04 | GSE104170 | GEO

Synergistic targeting of DNA-PK and KIT signaling pathways in KIT mutant acute myeloid leukemia

Project description:Acute Myeloid Leukemia (AML) is the most common and aggressive form of acute leukemia, with a 5-year survival rate of just 24%. Over a third of all AML patients harbor activating mutations in kinases, such as the receptor tyrosine kinases FLT3 and KIT. FLT3 and KIT mutations are associated with poor clinical outcomes and lower remission rates in response to standard-of-care chemotherapy. We have recently identified that the core kinase of the non-homologous end joining DNA repair pathway, DNA-PK, is activated downstream of FLT3; and targeting DNA-PK sensitized FLT3-mutant AML cells to standard-of-care therapies. Herein, we investigated DNA-PK as a possible therapeutic vulnerability in KIT mutant AML, using isogenic FDC-P1 myeloid progenitor cell lines transduced with an empty vector or oncogenic mutant KIT (V560G, D816V). Targeted quantitative phosphoproteomic profiling identified phosphorylation of DNA-PK at threonine 2599 in KIT mutant cells, indicative of DNA-PK activation. Accordingly, proliferation assays revealed that KIT mutant FDC-P1 cells were more sensitive to the DNA-PK inhibitors M3814 or NU7441, compared to empty vector controls. DNA-PK inhibition combined with inhibition of KIT signaling via using the kinase inhibitors dasatinib or ibrutinib, or the protein phosphatase 2A activators FTY720 or AAL(S), led to synergistic cell death. Discovery phosphoproteomic analysis of KIT-D816V cells revealed that dasatinib single-agent treatment inhibited ERK1 activity, and M3814 single-agent treatment inhibited Akt/mTOR activity. The combination of dasatinib and M3814 treatment inhibited both ERK/MAPK and Akt/mTOR activity, and induced synergistic inhibition of phosphorylation of transcription regulators including MYC and MYB. This study provides insight into the oncogenic pathways regulated by DNA-PK beyond its canonical role in DNA repair, and demonstrates that DNA-PK is a promising novel therapeutic target for KIT mutant cancers.

2023-01-26 | PXD030214 | panorama

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