CDKN2A remodels lipid metabolism to prime glioblastoma for ferroptosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA965892 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:CDKN2A remodels lipid metabolism to prime glioblastoma for ferroptosis
| PRJNA965893 | ENA
Project description:CDKN2A deletion remodels immune infiltrate in Diffuse Pleural Mesothelioma
| PRJNA1288417 | ENA
Project description:Tumor Acidosis Remodels the Glycocalyx to Control Lipid Scavenging and Ferroptosis
| PRJNA1279121 | ENA
Project description:Acute myeloid leukemia (AML) is a hematologic malignancy with a poor prognosis. We discovered that BMAL1 is a ferroptosis suppressor. Furthermore, it was also found to be overexpressed in AML patients, affecting the cell cycle and promoting tumor cell growth and progression. In this study, we further validated the association of BMAL1 with the progression and survival outcomes of AML. Lipidomic revealed that the levels of ceramide increased in AML cells following the depletion of BMAL1. Ceramide facilitated ferroptosis in AML cells. ASAH2 played a key role in this process. BMAL1 could not directly regulate ASAH2 but instead through IKZF2. Elevated levels of ceramide promoted the degradation of the ferroptosis protection molecule GPX4, ultimately promoting ferroptosis. Furthermore, ceramide treatment has been demonstrated to enhance the responsiveness of AML cells to sorafenib. In summary, this study elucidates that BMAL1 depletion remodels ceramide metabolism to regulate the sensitivity of AML cells to ferroptosis and targeted drug sorafenib.
2025-01-24 | MTBLS11557 | MetaboLights
Project description:Ferroptosis is an iron-dependent form of cell death driven by biochemical and metabolic alterations resulting in oxidation within the lipid compartment. Calcium is a potent signaling molecule ascribed to diverse cellular processes including migration, neurotransmitter function, and cell death. Here we elucidate a crucial link between calcium homeostasis and ferroptotic cell death through the identification of the tetraspanin MS4A15. Ectopic MS4A15 expression specifically protects against ferroptosis by depleting endoplasmic reticulum stores. In an unexpected connection, prolonged calcium dysregulation stimulates fundamental remodeling to ferroptosis-resistant monounsaturated and plasmalogen lipid species. Application of this discovery revealed that augmenting luminal calcium sensitizes cancer cell lines previously refractory to ferroptosis. This finding provides a unique mechanistic basis for ferroptosis sensitivity and resolves a long-standing query into the role of calcium in oxidative cell death. Manipulating calcium homeostasis offers an unprecedented strategy for overcoming therapy resistance in cancer.
2021-10-09 | GSE160574 | GEO
Project description:Ferroptosis is an iron-dependent regulated cell death caused by the accumulation of lipid peroxidation for the uncontrolled metabolism. Serum, as the major medium for the cultured cells, resembles the contents of the extracellular fluid in vivo and provides biomolecules for cellular metabolism. The efficiency of ferroptosis induction is influenced by several factors including the extracellular environment. However, the effect of serum on ferroptosis remains largely unclear. We found that cells cultured in different serums have varying efficiencies in ferroptosis induction. By purifying and identifying active serum components, we discovered that serum protein apolipoprotein H (APOH) play essential role in inhibiting ferroptosis. Moreover, APOH activates the phosphoinositide 3-kinase (PI3K)/AKT-Sterol regulatory element-binding proteins (SREBPs) pathway. SREBPs upregulate the stearoyl-CoA desaturase (SCD) increasing cellular monounsaturated fatty acid-containing phospholipids (MUFA-PLs), leading to ferroptosis inhibition. Our findings indicate that APOH, as an extracellular protein, plays an important role in cellular lipid metabolism and inhibition of ferroptosis, thus may having therapeutic applications in cancer treatment and ferroptosis-related diseases.
2024-10-09 | GSE237178 | GEO
Project description:Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate this form of cell death are needed. We applied two independent approaches, a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines to uncover acyl-CoA synthetase long-chain family member 4 (Acsl4) as an essential component for ferroptosis execution.
2017-06-01 | GSE86384 | GEO
Project description:Common genetic variants in a 58-kilobase (kb) region of chromosome 9p21, near the CDKN2A/B cell proliferation inhibitor genes, are strongly associated with coronary artery disease (CAD). We previously reported a congenic mouse model harboring an atherosclerosis susceptibility locus in a region of homology with the human 9p21 locus. We now report markedly decreased Cdkn2a (cyclin-dependent kinase inhibitor 2a) mRNA expression in macrophages and increased circulating levels of Ly6Chigh inflammatory monocytes in congenic mice compared to controls. A bone marrow (BM) transplantation study revealed that BM-derived cells from Cdkn2a+/- mice are capable of conferring accelerated atherosclerosis, increased inflammatory monocyte subsets and monocyte proliferation in the Ldlr-/- mouse model. These findings provide a mechanistic link between decreased expression of Cdkn2a transcripts, increased monocyte proliferation, and accelerated atherosclerosis. Aorta and macrophages from ten C57BL/6.MOLFc4(51Mb)-Ldlr-/- mice and their control C57BL/6-Ldlr-/- were obtained, RNA purified and hybridized to GPL9734 Affimetrix microarrays.
2011-09-30 | E-GEOD-24342 | biostudies-arrayexpress
Project description:Common genetic variants in a 58-kilobase (kb) region of chromosome 9p21, near the CDKN2A/B cell proliferation inhibitor genes, are strongly associated with coronary artery disease (CAD). We previously reported a congenic mouse model harboring an atherosclerosis susceptibility locus in a region of homology with the human 9p21 locus. We now report markedly decreased Cdkn2a (cyclin-dependent kinase inhibitor 2a) mRNA expression in macrophages and increased circulating levels of Ly6Chigh inflammatory monocytes in congenic mice compared to controls. A bone marrow (BM) transplantation study revealed that BM-derived cells from Cdkn2a+/- mice are capable of conferring accelerated atherosclerosis, increased inflammatory monocyte subsets and monocyte proliferation in the Ldlr-/- mouse model. These findings provide a mechanistic link between decreased expression of Cdkn2a transcripts, increased monocyte proliferation, and accelerated atherosclerosis.
2011-10-01 | GSE24342 | GEO
Project description:G-protein-coupled receptors (GPCRs) mediate most cellular responses to hormones, neurotransmitters as well as environmental stimulants. However, whether GPCRs participate in modulation of tissue homeostasis through ferroptosis remains unclear. By GPCR cDNA library screening, here we identify that GPR56/ADGRG1 remodels ferroptosis plasticity. Loss of GPR56 sensitizes cells to ferroptosis and deficiency of GPR56 deteriorates ferroptosis-mediated liver injury induced by Doxorubicin (DOX) or ischemia-reperfusion (IR). Mechanistically, GPR56 decreases the abundance of phospholipids containing free polyunsaturated fatty acids (PUFAs) by promoting endocytosis-lysosomal degradation of CD36. By screening a panel of steroid hormones, we identified that 17α-hydroxypregnenolone (17-OH PREG) acts as an agonist of GPR56 to antagonize ferroptosis and efficiently attenuates liver injury before or after insult. Moreover, disease associated GPR56 mutants were unresponsive to 17-OH PREG activation and insufficient to defend against ferroptosis. Together, our findings uncover that 17-OH PREG-GPR56 axis-mediated signal transduction works as a new anti-ferroptotic pathway to maintain liver homeostasis, providing novel insights into the potential therapy for liver injury.
2026-01-15 | GSE274998 | GEO