ATGL suppresses ferroptosis in acute myeloid leukemia cells via modulating the CEBPα/SCD1 axis and induces gilteritinib resistance.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE307476 | GEO | 2026/02/11
REPOSITORIES: GEO
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Project description:Lipid metabolism plays a central role in prostate cancer. To date, the major focus on prostate cancer lipid metabolism has centered on the roles of de novo lipogenesis and lipid uptake with little consideration for how cancer cells access these lipids once they are created or taken up and stored. Analysis of patient-derived phosphoproteomics data identified adipose triglyceride lipase (ATGL), a rate-limiting enzyme in the breakdown of triglycerides and previously suspected tumor suppressor, as a target of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)-AMP-dependent protein kinase (AMPK) signaling that, conversely, promotes castration-resistant prostate cancer (CRPC) progression. Phosphorylation of ATGL by CAMKK2-AMPK signaling increased ATGL’s lipase activity, cancer cell proliferation, migration, and invasion. Shotgun lipidomics and imaging mass spectrometry demonstrated ATGL’s profound regulation of prostate cancer lipid metabolism in vitro and in vivo, remodeling membrane composition. Targeting ATGL using molecular, genetic, and/or pharmacological approaches impaired the growth of human and murine prostate cancer cells in culture and xenograft mouse models of CRPC as well as organoid models. The efficacy of ATGL inhibition occurs in a glucose concentration-dependent manner. Accordingly, pharmacological inhibition or depletion of ATGL induced metabolic plasticity with a shift towards glycolysis, which could be exploited therapeutically by co-targeting both metabolic pathways. Together, these data nominate ATGL and intracellular lipolysis as a potential therapeutic target for the treatment of CRPC and provide insights for future combination therapies.
2023-11-22 | GSE243159 | GEO
Project description:ATGL suppresses ferroptosis in acute myeloid leukemia cells via modulating the CEBPα/SCD1 axis and induces gilteritinib resistance.
| PRJNA1321789 | ENA
Project description:Gene expression profiling in 6 tissues (white adipose tissue (WAT), brown adipose tissue (BAT), cardiac muscle (CM), liver (LIV), kidney (KID), skeletal muscle (SM)) from ATGL(-/-) mice versus wildtype (ATGL+/+) mice.
2008-02-03 | E-MARS-8 | biostudies-arrayexpress
Project description:ATGL= the rate-limiting enzyme for intracellular lipolysis. Atgl KO/cTg = Mice lacking Atgl except for cardiac transgenic overexpression of Atgl (Atgl -/- ,Myh6Atgl+/+) to rescue early age death deu to cardiomyopathy. wt/cTg = respective control. The airways of the lung are constantly exposed to inhaled toxic substances, resulting in cellular damage. Within bronchii, club cells make up majority of the cell population in the terminal bronchiolar epithelia. Club cells are known for their ability to metabolize environmental toxins and constantly repairing small impacts in the epithelial layer. Considering the importance of club cells in maintaining bronchiolar epithelial integrity, we porformed gene expression data analysis to decipher the possible dysregulated gene expression thereby corresponding molecular pathways in our mice lacking ATGL.
2021-05-28 | GSE175659 | GEO
Project description:ATGL is the key enzyme in intracellular lipolysis playing a critical role in metabolic and cardiovascular diseases. ATGL is tightly regulated through a known set of protein-protein interaction partners with activating or inhibiting functions in control of lipolysis. However, the binding mode and protein interaction sites of ATGL and its partners are unknown. Using deep mutational protein interaction perturbation scanning we generated comprehensive profiles of single amino acid variants effecting the interactions of ATGL with its regulatory partners: CGI-58, G0S2, PLIN1, PLIN5 and CIDEC. Twenty-three ATGL variants gave a specific interaction perturbation pattern when validated in co-immunoprecipitation experiments in mammalian cells. We identified and characterized eleven, highly selective ATGL “switch” mutations which affect the interaction of one of the five partners without affecting the others. Switch mutations thus provided distinct interaction determinants for ATGL’s key regulatory proteins at an amino acid resolution. When tested for triglyceride hydrolase activity in vitro and lipolysis in cells, the activity patterns of the ATGL switch variants traced to their protein interaction profile. In the context of structural data, the integration of variant binding and activity profiles provided important insights into lipolysis regulation and the impact of mutations in human disease.
2024-03-14 | PXD049436 | Pride
Project description:Adipose Triglyceride Lipase (ATGL) and Monoglyceride Lipase (MGL) are two enzymes that contribute to intracellular neutral lipolysis by breaking down triglycerides stored within lipid droplets. Recently, lipid droplet accumulation has been described as a novel hallmark of cancer. While lipid metabolism has been investigated in cancer in recent decades, the role of lipid hydrolysis and its enzymes have not been in the focus of cancer research. We and others have found that lipid hydrolysis enzymes might play an important role in the development and progression of lung cancer. To this end, we chose four different non-small cell lung cancer cell lines and employed CRISPR-Cas9 gene editing to knock out either ATGL (ATGL-KO) or MGL (MGL-KO), and a non-targeting control (NTC) was employed to generate a control cell line within each parental cell type. We then performed label free quantitative proteomics to identify differences between the generated cell lines and confirmed ATGL-KO in ATGL-KO cell lines as well as MGL-KO in MGL-KO cell lines. Furthermore, dihydroorotate dehydrogenase (DHODH), an enzyme that is important in some cancer, was upregulated in some, but not all, of the NSCLC cancer cell lines lacking either one of the two lipases.
2023-11-27 | PXD046912 | Pride
Project description:To investigate the role of ATGL in endothelial cell function, we knockdown ATGL with siRNA and compared with siCTL. We then performed gene expression profiling analysis using data obtained from RNA-seq of 3 different samples each condition.
2023-11-03 | GSE231619 | GEO
Project description:Atglflox/flox (B6N.129S-Pnpla2tm1Eek/J), S100A8-cre+/- (B6.Cg-Tg(S100A8-cre,-EGFP)1Ilw/J) mice were obtained from The Jackson Laboratory. Atglflox/flox mice were bred to S100A8-cre+/- mice to generate Atglflox/WTS100A8-cre+/- mice, which were backcrossed onto Atglflox/flox mice to generate Atglflox/floxS100A8-cre+/- mice (Atgl neutrophils-specific knock out, Atgl-cKO). Age-matched littermate Atglflox/flox mice were used as wild-type (WT) controls. To compare of the gene expression of the lung-infiltrating neutrophils isolated from Atgl-cKO mice and their WT littermates, AT3-g-csf cells were injected into the fourth mammary fat pads of female WT and Atgl-cKO mice (10-week-old, n = 4/group). The AT3-g-csf cell line is based on a murine breast cancer cell line (AT3) derived from MMTV-PyMT tumors in the C57BL/6 background, and further constructed to overexpress granulocyte-colony stimulating factor (G-CSF) for induction of the host inflammatory condition. At day 10 (pre-metastatic stage), the mice were euthanized and then Ly6G+ neutrophils were isolated from lung by using anti-Ly6G MicroBead Kit (Miltenyi Biotec) following manufacturer’s instructions. The isolated neutrophils were analyzed by flow cytometry and the cells with a > 95% purity were used for the next procedure. Total RNA was isolated from neutrophils using the miRNeasy Mini kit (Qiagen) and the transcriptional profiles of neutrophils were analyzed by RNA sequencing.
2020-06-28 | E-MTAB-9235 | biostudies-arrayexpress
Project description:Obesity is a worldwide epidemic associated with increased risk and progression of colon cancer. Here, we aimed to determine the role of adipose triglyceride lipase (ATGL), responsible for intracellular lipid droplet (LDs) utilization, in obesity driven colonic tumorigenesis. In local colon cancer patients, significantly increased ATGL levels in tumor tissue, compared to controls, were augmented in obese individuals. Elevated ATGL levels in human colon cancer cells (CCC) relative to non-transformed were augmented by an obesity mediator, oleic acid (OA). In CCC and colonospheres, enriched in colon cancer stem cells (CCSC), inhibition of ATGL prevented LDs utilization and inhibited OA-stimulated growth through retinoblastoma-mediated cell-cycle arrest. Further, transcriptomic analysis of CCC, with inhibited ATGL, revealed targeted pathways driving tumorigenesis and high-fat-diet obesity facilitated tumorigenic pathways. Inhibition of ATGL in colonospheres revealed targeted pathways in human colonic tumor crypt base cells (enriched in CCSC) derived from colon cancer patients. In CCC and colonospheres, we validated selected transcripts targeted by ATGL inhibition, some with emerging roles in colonic tumorigeneses (ATG2B, PCK2, PGAM1, SPTLC2, IGFBP1, ABCC3) and others with established roles (MYC, MUC2). These findings demonstrate obesity-promoted, ATGL-mediated colonic tumorigenesis and establishes therapeutic significance of ATGL in obesity reinforced colon cancer progression.
2022-02-05 | GSE195994 | GEO
Project description:Animals often face food scarcity in nature. In order to survive, some animals store substantial fat when food is available. However, the physiological mechanism by which they store substantial fat and maintain metabolic health in the short term is poorly understood. Here, using the grass carp (Ctenopharyngodon idellus) as a model, which exhibits remarkable fat storage capacity, we found that adipose tissue responded to energy overload first and expanded through adipocyte hypertrophy and hyperplasia. Mechanistically, hypoxia inducible factor-1αa (hif-1αa) was activated in mature adipocytes after short-term high-energy intake, thereby bidirectionally regulating adipose triglyceride lipase (atgl) to drive healthy expansion of adipose tissue in grass carp: (1) Hif-1αa downregulates atgl protein levels via the ubiquitin-proteasome pathway, promoting adipocyte hypertrophy; (2) Hif-1αa upregulates atgl transcription to sustain basal lipolysis, releasing free fatty acids that activate peroxisome proliferator-activated receptor γ (pparγ) in preadipocytes to promote adipocyte hyperplasia. This crosstalk-mediated rapid adipocyte hyperplasia prevents detrimental excessive hypertrophy and significantly boosts the overall energy storage capacity. Taken together, our study reveals how grass carp utilize hypoxia signals (a signal often associated with metabolic disorders in mammals) to coordinate the pattern of adipose tissue expansion, achieving rapid and healthy lipid storage. Our findings redefine hypoxia's role as a metabolic orchestrator rather than a stress indicator, suggesting potential implications for a theoretical basis for addressing obesity-related diseases in humans and farmed animals caused by excessive energy intake.
2026-03-04 | GSE315218 | GEO