Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Plasticity of ether lipids promotes ferroptosis susceptibility and evasion

ABSTRACT: Ferroptosis, an iron-dependent, non-apoptotic cell death program, is involved in a variety of degenerative diseases and represents a targetable vulnerability in certain cancers. The ferroptosis-susceptible cell-state can either preexist in cells arising from certain lineages or be acquired during cell-state transitions. Precisely how ferroptosis susceptibility is dynamically regulated remains poorly understood. Using genome-wide CRISPR/Cas9 suppressor screens, we identify a key role for peroxisome–ether phospholipid genes in driving ferroptosis susceptibility and evasion in ovarian cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE151062 | GEO | 2020/09/16

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Plasticity of ether lipids promotes ferroptosis susceptibility and evasion

Project description:Plasticity of ether lipids promotes ferroptosis susceptibility and evasion

| PRJNA634531 | ENA

Plasticity of ether lipids promotes ferroptosis susceptibility and evasion.

Project description: Not available

| S-EPMC8051864 | biostudies-literature

Biosynthesis of membrane-spanning ether lipids in Thermotoga maritima

Project description:This study was conducted to identify the genes involved in the synthesis of membrane-spanning ether lipids in Thermotoga maritima MSB8.

2022-10-26 | GSE211547 | GEO

Endothelial ether lipids link blood vessels to neurodegeneration

Project description:Vascular disease contributes to neurodegeneration, which is associated with decreased blood pressure in older humans. Plasmalogens, ether phospholipids produced by peroxisomes, are decreased in Alzheimer’s disease, Parkinson’s disease and other neurodegenerative disorders. Here we show that endothelium-derived ether phospholipids affect blood pressure, behavior, and neurodegeneration in mice. In young adult mice, inducible endothelial-specific disruption of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, unexpectedly decreased circulating plasmalogens. PexRAP Endothelial KnockOut (PEKO) mice responded normally to hindlimb ischemia but had lower blood pressure and increased plasma renin activity. In PEKO as compared to control mice, tyrosine hydroxylase was decreased in the locus coeruleus, which maintains blood pressure and arousal. PEKO mice moved less, slept more, and had impaired attention to and recall of environmental events as well as mild spatial memory deficits. In PEKO hippocampus, gliosis was increased and a plasmalogen associated with memory was decreased. Despite lower blood pressure, PEKO mice had generally normal homotopic functional connectivity by optical neuroimaging of the cerebral cortex. Decreased GSK3 phosphorylation, a marker of neurodegeneration, was detected in PEKO cerebral cortex. In a co-culture system, PexRAP knockdown in brain endothelial cells decreased GSK3 phosphorylation in co-cultured astrocytes that was rescued by incubation with the ether lipid alkylglycerol. Our findings suggest that the endothelium is a source of complex lipids that confer neuroprotection in mice.

2021-09-10 | PXD024116 | Pride

Biosynthesis of membrane-spanning ether lipids in Thermotoga maritima.

Project description:This study was conducted to identify the proteins involved in the synthesis of membrane-spanning ether lipids in Thermotoga maritima.

2023-10-03 | PXD035794 | Pride

Cell density-dependent ferroptosis in breast cancer is induced by accumulation of polyunsaturated fatty acid-enriched triacylglycerides

Project description:Ferroptosis is a regulated form of necrotic cell death caused by iron-dependent phospholipid peroxidation. It can be induced by inhibiting glutathione peroxidase 4 (GPX4), the key enzyme for efficiently reducing peroxides within phospholipid bilayers. Recent data suggest that cancer cells undergoing EMT (dedifferentiation) and those resistant to standard therapy expose a high vulnerability toward ferroptosis. Although recent studies have begun to identify and characterize the metabolic and genetic determinants underlying ferroptosis, many mechanisms that dictate ferroptosis sensitivity remain unknown. Here, we show that low cell density sensitizes primary mammary epithelial and breast cancer cells to ferroptosis induced by GPX4 inhibition, whereas high cell density confers resistance. These effects occur irrespective of oncogenic signaling, cellular phenotype and expression of the fatty acid ligase acyl-CoA synthetase long chain family member 4 (ACSL4). By contrast, we show that a massive accumulation of neutral triacylglycerides (TAG) enriched with polyunsaturated fatty acids (PUFA) is induced at low cell density. In addition, de novo lipogenesis and desaturation pathways were found to be reduced at low cell density, indicative of increased fatty acid uptake. Our study suggests that PUFA-mediated toxicity is limited by the enrichment in TAGs that in turn might pose a vulnerability towards ferroptosis. Conclusively, cell density regulates lipid metabolism of breast epithelial and cancer cells, which results in a ferroptosis-sensitive cell state with the potential to be exploited therapeutically during metastatic dissemination.

2020-11-13 | PXD016276 | Pride

Proteomic analysis of U2OS cells treated with the dihydroorotate dehydrogenase (DHODH) inhibitor Brequinar

Project description:The mitochondrial respiratory chain assembles into higher order complexes termed supercomplexes (SCs) under certain physiological or metabolic stimuli. A small molecule screen developed by the lab identified DHODH inhibitors as potent activators of SC assembly in cancer cells. To investigate the proteomic regulation of SCs under nucleotide deficiency, we treated U2OS cells for 48 hours with Brequinar (500 nM). Proteomic analysis highlighted strong signatures of respiratory chain subunit abundance and peroxisomal-derived ether phospholipid synthesis enzymes. Bypassing DHODH inhibition through uridine supplementation prevented these alterations. These findings establish a coordinated cellular response to reduced nucleotide pools that stimulates ether phospholipid synthesis and respiratory chain supra-assembly.

2022-02-16 | PXD023882 | Pride

Ferroptosis inhibition by oleic acid mitigates iron-overload-induced injury

Project description:Iron overload, characterized by accumulation of iron in tissues, induces a multiorgan toxicity whose mechanisms are not fully understood. Using cultured cell lines, Caenorhabditis elegans, and mice, we found that ferroptosis occurs in the context of iron-overload-mediated damage. Exogenous oleic acid protected against iron-overload-toxicity in cell culture and Caenorhabditis elegans by suppressing ferroptosis. In mice, oleic acid protected against FAC-induced liver lipid peroxidation and damage. Oleic acid changed the cellular lipid composition, characterized by decreased levels of polyunsaturated fatty acyl phospholipids and decreased levels of ether-linked phospholipids. The protective effect of oleic acid in cells was attenuated by GW6471 (a PPAR- antagonist), as well as in Caenorhabditis elegans lacking the nuclear hormone receptor NHR-49 (a PPAR- functional homologue). These results highlight ferroptosis as a driver of iron-overload-mediated damage, which is inhibited by oleic acid. This monounsaturated fatty acid represents a potential therapeutic approach to mitigating organ damage in iron overload individuals.

2023-10-02 | GSE243891 | GEO

Darapladib, an inhibitor of Lp-PLA2, sensitises cancer cells to ferroptosis by remodelling lipid metabolism

Project description:Arachidonic and adrenic acids in the membrane play key roles in ferroptosis, but how these fatty acids are manipulated in cells is largely unknown. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen revealed that darapladib, an inhibitor of Lp-PLA2, synergistically induced ferroptosis in the presence of GPX4 inhibitors. Notably, darapladib was able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, Lp-PLA2 was located in the membrane and cytoplasm and suppressed ferroptosis, suggesting the critical role of intracellular Lp-PLA2. Lipidomic analysis showed that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriched phosphatidylethanolamine (PE) species and reduced lysophosphatidylethanolamine (lysoPE) species. Moreover, combination treatment with darapladib and PACMA31, a GPX4 inhibitor, efficiently inhibited tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.

2023-10-24 | PXD044002 | Pride

MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis

Project description:<p>Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially those containing the polyunsaturated fatty acid arachidonic acid (AA), is central in driving ferroptosis. Here, we reveal that an understudied Golgi-resident scaffold protein, MMD, promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner. Mechanistically, MMD physically interacts with both ACSL4 and MBOAT7, two enzymes that catalyze sequential steps to incorporate AA in phosphatidylinositol (PI) lipids. Thus, MMD increases the flux of AA into PI, resulting in heightened cellular levels of AA-PI and other AA-containing phospholipid species. This molecular mechanism points to a pro-ferroptotic role for MBOAT7 and AA-PI, with potential therapeutic implications, and reveals that MMD is an important regulator of cellular lipid metabolism.</p>

2023-09-06 | MTBLS8280 | MetaboLights

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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