Endocannabinoid biosynthetic enzymes regulate pain response via LKB1-AMPK signaling
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ABSTRACT:
PROVIDER: PRJNA1048496 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR27054371_1.fastq.gz | Fastqsanger.gz | |||
| SRR27054371_2.fastq.gz | Fastqsanger.gz | |||
| SRR27054372_1.fastq.gz | Fastqsanger.gz | |||
| SRR27054372_2.fastq.gz | Fastqsanger.gz | |||
| SRR27054373_1.fastq.gz | Fastqsanger.gz |
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Project description:Diacylglycerol lipase-beta (DAGLB) serves as a principal 2-arachidonoylglycerol (2-AG) biosynthetic enzyme regulating endocannabinoid and eicosanoid metabolism in immune cells including macrophages and dendritic cells. Genetic or pharmacological inactivation of DAGLb ameliorates inflammation and hyper-nociception in preclinical models of pathogenic pain. These beneficial effects have been assigned principally to reductions in downstream pro-inflammatory lipid signaling, leaving alternative mechanisms of regulation largely underexplored. Here, we apply quantitative chemical- and phospho-proteomics to discover that disruption of DAGLb in primary macrophages leads to LKB1-AMPK signaling activation, resulting in reprogramming of the phosphoproteome and bioenergetics. Notably, AMPK inhibition reversed the antinociceptive effects of DAGLb blockade, thereby directly supporting DAGLβ-AMPK crosstalk in vivo. Our findings uncover signaling between endocannabinoid biosynthetic enzymes and ancient energy sensing kinases to mediate cell biological and pain responses.
2024-01-02 | GSE249312 | GEO
Project description:Diacylglycerol lipase-beta (DAGLβ) serves as a principal 2-arachidonoylglycerol (2-AG) biosynthetic enzyme regulating endocannabinoid and eicosanoid metabolism in immune cells including macrophages and dendritic cells. Genetic or pharmacological inactivation of DAGLβ ameliorates inflammation and hyper-nociception in preclinical models of pathogenic pain. These beneficial effects have been assigned principally to reductions in downstream proinflammatory lipid signaling, leaving alternative mechanisms of regulation largely underexplored. Here, we apply quantitative chemical- and phospho-proteomics to find that disruption of DAGLβ in primary macrophages leads to LKB1–AMPK signaling activation, resulting in reprogramming of the phosphoproteome and bioenergetics. Notably, AMPK inhibition reversed the antinociceptive effects of DAGLβ blockade, thereby directly supporting DAGLβ–AMPK crosstalk in vivo. Our findings uncover signaling between endocannabinoid biosynthetic enzymes and ancient energy-sensing kinases to mediate cell biological and pain responses.
2024-01-02 | PXD047413 | Pride
Project description:RNA-Seq was performed on pancreatic islets from four transgenic mouse strains affecting LKB1 and AMPK. A conditional LKB1 knockout strain was generated. Double conditional knockouts for AMPK alpha1 and AMPK alpha2 were also generated. These conditional strains were crossed with RIP-Cre (driven by rat insulin promoter) or Ins1-Cre mice to generate LKB1 knockout and AMPK double knockout strains.
2014-10-25 | E-MTAB-2791 | biostudies-arrayexpress
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:Purpose: Mutations in STK11 (LKB1) occur in 17% of lung adenocarcinoma (LUAD) and drive a suppressive (cold) tumor immune microenvironment (TME) and resistance to immunotherapy. The mechanisms underpin the establishment and maintenance of a cold TME in LKB1 mutant LUAD remain poorly understood and the identification of downstream effectors is critical to inform therapeutic strategies to invigorate antitumor immunity. In this study, we investigated the association between inactivation of AMPK, one of the downstream substrates of LKB1, and immune evasion in human LUAD as well as the causal role of AMPK on TME in genetically engineered mouse model (GEMM) of LUAD. Experimental Design: We modeled AMPK inactivation in vivo using GEMM by deleting both AMPKα1 (Prkaa1) and AMPKα2 (Prkaa2) in KrasG12D-driven LUAD (KAA). Furthermore, we investigated the impact of AMPK inactivation on immune cell infiltration and global gene-expression programs of murine LUAD. Gene expression signature from AMPK-deficient murine LUAD was further compared to that of Lkb1 deficient murineLUAD as well as human LUAD with either LKB1 mutation or attenuated AMPK phosphorylation. Results: Inactivation of both AMPKα1 and AMPKα2 accelerates KrasG12D-driven LUAD. AMPK-deficient tumors are characterized with reduced infiltration of CD8+/CD4+ T cells and gene signatures associated with compromised immune microenvironment, which resembles LKB1-deficient murine and human LUAD (KL) as well as LKB1-wildtype LUAD with reduced AMPK phosphorylation. Attenuation of the MHC Class 1 component ß2 microglobulin (ß2M) was identified as a shared feature in KL and KAA murine LUAD as well as in human LUAD with either LKB1 mutations or reduced AMPK phosphorylation. Furthermore, reactivation of AMPK by expression of constitutive active form of AMPKα1 leads to restoration of ß2M level in LKB1 mutant LUAD cells. Conclusions: The results identify attenuation of the LKB1 substrate AMPK as an important mechanism for decreased MHC Class 1 expression and immune evasion in LKB1 mutant LUAD. Translational relevance: LKB1 loss-of-function mutations rank as the third most common genetic alterations found in lung adenocarcinoma and associated with immune evasion. In the current study, on the basis of GEMM of LUAD we established the causal relationship between inactivation of the LKB1 substrate AMPK and immune evasion. Furthermore we find that the status of AMPK phosphorylation is more sensitive than LKB1 mutation in predicting impaired tumor immune microenvironment and likely also for the resistance to immunotherapy. The results also suggest that restoration of AMPK activity could increase the number of patients benefiting from immunotherapy.
2022-01-26 | GSE175479 | 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:The 5' AMP-activated protein kinase (AMPK) is a master energy sensing kinase that is regulated by phosphorylation of Thr172 in its activation loop. Three kinases can phosphorylate AMPK at Thr172: the tumor suppressor LKB1, CAMKK2 and TAK1. While LKB1- and CAMKK2-mediated AMPK Thr172 phosphorylation have been well-characterized, much less is known about TAK1-dependent AMPK phosphorylation. An important target of TAK1 is IκB kinase (IKK) which controls NF-B transcription factor activation. Here, we tested the hypothesis that IKK acted downstream of TAK1 to activate AMPK by phosphorylating Thr172. IKK was required for phosphorylation of Thr172 in AMPK in response to treatment with IL-1 or TNF- treatment or by TAK1 overexpression. Additionally, IKK regulated basal AMPK Thr172 phosphorylation in several cancer cell types independently of TAK1, indicating that other modes of IKK activation could lead to AMPK activation. We found that IKK directly phosphorylated AMPK at Thr172 independently of LKB1 or energy stress. This finding indicated that while LKB1 activates AMPK as a sensor of energetic stress, IKK activated AMPK in response to extracellular inflammatory signals and through distinct pathways downstream of IKK activation. Accordingly, in LKB1-deficient cells, IKK inhibition caused a reduction in AMPK Thr172 phosphorylation in response to the mitochondrial inhibitor phenformin. This response led to enhanced apoptosis and suggests that IKK inhibition in combination with phenformin could be used clinically to treat patients with LKB1-deficient cancers.
2018-07-16 | PXD009897 | 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:LKB1 encodes a Ser/Thr kinase and acts as an evolutionarily conserved sensor of cellular energy status in eukaryotic cells. LKB1 functions as the major upstream kinase to phosphorylate AMPK and 12 other AMPK-related kinases, which is required for their activation in many cellular contexts. Once activated, AMPK and AMPK-related kinases phosphorylate a diverse array of downstream effectors to switch on ATP-generating catabolic processes and switch off ATP-consuming anabolic processes, thus restoring energy balance during periods of energetic stress. To study the role and mechanisms of Lkb1 in the regulation of hematopoietic stem cell (HSC) biology, we performed transcriptome analysis of sorted LSK (Lin-, Sca-1+, c-Kit+) cells from Lkb1 WT and KO bone marrows at 1 day post-completing tamoxifen injection (DPI). To identify more proximal molecular effects, we chose 1 DPI due to the modest phenotypes in Lkb1 KO mice, yet documentation of efficient Lkb1 deletion in LSK cells at this very early time point. We treated Lkb1 L/L rosa26CreERT2 and Lkb1 L/L mice (C57BL/Ka-CD45.2:Thy-1.1 background) with Tamoxifen for 5 days to somatically delete Lkb1 in adult mice, and generated Lkb1 WT and KO mice. At 1 DPI, we prepared single-cell suspensions from bone marrow (from femoral and tibial bones), and stained and sorted LSK populations using FACSAria (Becton Dickinson, Mountain View, CA). The RNA was extracted from sorted LSK cells, amplified and subjected to gene profiling. The samples include 3 Lkb1 WT (Lkb1 WT 5-7) and 4 Lkb1 KO (Lkb1 KO 4-7) replicates.
2010-12-01 | E-GEOD-24765 | biostudies-arrayexpress