Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA882385 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:PROX1 Orchestrates Tumor Metabolic Plasticity by Integrating LKB1-AMPK Signaling with BCAA Catabolism
| PRJNA884334 | ENA
Project description:PROX1 Orchestrates Tumor Metabolic Plasticity by Integrating LKB1-AMPK Signaling with BCAA Catabolism (RNA-Seq)
| PRJNA884342 | ENA
Project description:PROX1 Orchestrates Tumor Metabolic Plasticity by Integrating LKB1-AMPK Signaling with BCAA Catabolism (ATAC-Seq)
| PRJNA884343 | ENA
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
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 | GSE214193 | GEO
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 | GSE214192 | GEO
Project description:The serine/threonine kinase LKB1 is a tumor suppressor gene which also plays key roles in metabolic function in peripheral tissues through its direct phosphorylation and activation of the AMP-activated protein kinase (AMPK). The LKB1/AMPK pathway plays key roles in the liver in suppressing transcriptional programs of gluconeogenesis and lipogenesis, and hepatic LKB1 is required for the ability of the type 2 diabetes agent metformin to lower blood glucose levels in mice. To more broadly define how the LKB1/AMPK pathway controls hepatic metabolism, transcriptional profiling was employed using mice with an inducible liver-specific deletion of Lkb1. Unexpectedly, LKB1/AMPK signaling broadly controls the expression of many phase I xenobiotic metabolism genes, including several members of the cytochrome P450 family. In particular, expression of CYP2E1, an important mediator of drug detoxification, was markedly reduced upon LKB1 loss. LKB1 liver-specific knockout mice exposed to hepatocarcinogens, exhibited marked resistance to carcinogen-induced hepatocyte apoptosis, proliferation, senescence, and liver fibrosis and tumorigenesis.
2019-05-01 | GSE21984 | GEO
Project description:Adipose tissue is a metabolic and endocrine organ that secretes numerous bioactive molecules called adipocytokines. Among these, adiponectin has been argued to have a crucial role in obesity-associated breast cancer. The key molecule of adiponectin signaling is AMP-activated protein kinase (AMPK), mainly activated by Liver Kinase B1 (LKB1). Here, we demonstrated how the ERalfa/LKB1 interaction may negatively interfere with the capability of LKB1 to phosphorylate AMPK and then inhibit its downstream signaling TSC2/mTOR/p70S6k. In MCF-7 cells upon adiponectin AMPK signaling was not working, keeping its downstream protein Acetyl-CoA Carboxylase (ACC) still active. In contrast, in MDA-MB-231 cells the phosphorylation of AMPK and ACC was enhanced with consequent inhibition of both lipogenesis and cell growth. Thus, upon adiponectin, ERalfa signaling switched the energy balance of breast cancer cells towards a lipogenic phenotype. In other words, adiponectin in all the concentrations tested played an inhibitory role on ERalpha-negative breast cancer cell growth and progression either in vitro or in vivo. In contrast, low adiponectin levels, similar to those circulating in obese patients, worked on ERalfa-positive cells as a growth factor, stimulating their growth and progression. The latter effect seems to be blunted in vivo only in the presence of high adiponectin concentration. Based on the present results, it can be concluded that if we prospectively address adiponectin as a pharmacological tool, a separate therapeutic treatment should be carefully assessed in ERalfa-positive and negative breast-cancer patients.
2020-02-27 | E-MTAB-6120 | biostudies-arrayexpress
Project description:Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter plays a key role in coordinating metabolic homeostasis by regulating TCA cycle activation, mitochondrial fatty acid oxidation and cellular calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial metabolic pathways has remained unexplored. Here, we investigate metabolic consequences of uniporter loss- and gain-of-function using uniporter knock out cells and the liver cancer fibrolamellar carcinoma (FLC), which we demonstrate to have elevated mitochondrial calcium levels. Our results reveal that branched chain amino acid (BCAA) catabolism and the urea cycle are uniporter-regulated metabolic pathways. Reduced uniproter function increases expression of BCAA catabolism genes, and the urea cycle enzyme ornithine transcarbamylase (OTC). In contrast, high uniporter activity in FLC suppresses their expression. This suppression happens via the transcription factor KLF15, a master regulator of liver metabolism, suggesting that calcium signaling plays a central role in FLC-associated metabolic changes, including hyperammonemia. Consistent with this, activation of BCAA catabolism in FLC cells impairs their growth. Collectively, our study identifies an important role for mitochondrial calcium signaling in metabolic adaptation through transcriptional regulation of metabolism and elucidates its importance for BCAA and ammonia metabolism in FLC.
2024-11-21 | MSV000096493 | MassIVE
Project description:Branched-chain amino acids (BCAA) have emerged as predictors of type 2 diabetes (T2D). However, their potential role in the pathogenesis of insulin resistance and T2D remains unclear. By integrating data from skeletal muscle gene expression and metabolomic analyses, we demonstrate evidence for perturbation in BCAA metabolism and fatty acid oxidation in skeletal muscle from insulin-resistant humans. Experimental modulation of BCAA flux in cultured cells alters fatty acid oxidation in parallel. Furthermore, heterozygosity for the BCAA metabolic enzyme methylmalonyl-CoA mutase (MUT) alters muscle lipid metabolism in vivo, resulting in increased muscle triacylglycerol (TAG) accumulation and increased body weight after high-fat feeding. Together, our results demonstrate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by reducing fatty acid oxidation and increasing TAG accumulation.
2017-02-09 | GSE66766 | GEO