3D gene regulation network in glioma ferroptosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE236253 | GEO | 2023/10/23
REPOSITORIES: GEO
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Project description:Ferroptosis is a form of regulated cell death that can be induced by inhibition of the cystine-glutamate antiporter, system xc-. Among the existing system xc- inhibitors, imidazole ketone erastin (IKE) is a potent, metabolically stable inhibitor of system xc- and inducer of ferroptosis potentially suitable for in vivo applications. We investigated the pharmacokinetic and pharmacodynamic features of IKE in a diffuse large B cell lymphoma (DLBCL) xenograft model and demonstrated that IKE exerted an antitumor effect by inhibiting system xc-, leading to glutathione depletion, lipid peroxidation, and the induction of ferroptosis biomarkers both in vitro and in vivo. Using untargeted lipidomics and qPCR, we identified distinct features of lipid metabolism in IKE-induced ferroptosis. In addition, biodegradable polyethylene glycol-poly(lactic-co-glycolic acid) nanoparticles were employed to aid in IKE delivery and exhibited reduced toxicity compared with free IKE in a DLBCL xenograft model.
2019-04-17 | MTBLS774 | MetaboLights
Project description:Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and
plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is
highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient
availability remains unclear. In this study, integrated proteomic and functional analyses reveal
that SLC7A11-mediated cystine uptake promotes not only GSH synthesis but also GPX4 protein synthesis. Mechanistically, cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the mTORC1-4E-BP signaling axis. Pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers (FINs) to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a hitherto unrecognized regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest to use the combination of mTORC1 inhibitors and FINs in cancer treatment.
2020-08-25 | MSV000086009 | MassIVE
Project description:Here, gene profiles in rat spermatogonial stem cell lines are compared to publicly available mouse, monkey and human spermatogonial gene profiles. Interestingly, rat spermatogonia expressed metabolic control factors Foxa1, Foxa2 and Foxa3. Germline Foxa2 was enriched in Gfra1Hi and Gfra1Low undifferentiated A-single spermatogonia. Foxa2-bound loci in spermatogonial chromatin were over-represented by conserved stemness genes (Dusp6, Gfra1, Etv5, Rest, Nanos2, Foxp1) that intersect bioinformatically with conserved glutathione/pentose phosphate metabolism genes (Tkt, Gss, Gclc, Gclm, Gpx1, Gpx4, Fth), marking elevated spermatogonial GSH:GSSG. Cystine-uptake and intracellular conversion to cysteine typically couple glutathione biosynthesis to pentose phosphate metabolism. Rat spermatogonia, curiously, displayed poor germline stem cell viability in cystine-containing media, and, like primate spermatogonia, exhibited reduced transsulfuration pathway markers. Exogenous cysteine, cysteine-like mercaptans, somatic testis cells and ferroptosis inhibitors counteracted the cysteine starvation-induced spermatogonial death and stimulated spermatogonial growth factor activity in vitro.
2020-12-17 | GSE163302 | GEO
Project description:Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We show that OTU deubiquitinase 5 (OTUD5) is a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. In this work, our study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.
2023-11-29 | GSE244330 | GEO
Project description:Triple-negative breast cancer (TNBC) has a highly aggressive nature and distinct molecular characteristics from other subtypes of breast cancer and lacks effective targeted therapy. The molecular and genetic basis of cysteine/cystine dependency in TNBC is complex. We found that cysteine addiction associates with the expression of a set of Claudin genes in TNBC. The Claudin-high TNBCs are independent on cystine, while the Claudin-low TNBCs undergo rapid ferroptosis upon cystine deprivation or inhibition of cystine transport by erastin. To overcome the resistance of Claudin-high TNBC and luminal breast cancer to the potential targeted cystine-addiction therapy, we explored the synthetic lethality of cysteine by an epigenetic compound library screen. Several potent HDAC6 inhibitors were identified and rendered the Claudin-high TNBCs and luminal cancer cells dependent on extracellular cystine and undergoing ferroptosis upon cystine deprivation. The transcriptomic profiling showed that the HDAC6 inhibitor tubacin in combination with erastin activates a synthetic-lethal transcriptional program. Together, we have identified the HDAC6 inhibitors as potent therapy-sensitizers to revive the targeted cysteine-addiction therapy for various subtypes of breast cancer, not limit in the Claudin-low TNBC.
2021-06-02 | GSE154425 | GEO
Project description:Ferroptosis is associated with lipid hydroperoxides generated by oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. We identified conjugated linoleates including α-eleostearic acid (αESA) as novel ferroptosis inducers. αESA did not alter GPX4 activity but was incorporated into cellular lipids and promoted lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death was mediated by acyl-CoA synthetase long-chain isoform 1, which promoted αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppressed ferroptosis triggered by αESA but not by GPX4 inhibition. Orally administered tung oil, naturally rich in αESA, limited tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a novel approach to ferroptosis, complementary to GPX4 inhibition, with therapeutic potential.
2021-02-08 | GSE162069 | GEO
Project description:Analysis of ferroptosis markers from cells isolated from neuroblastoma orthotopic xenograft mouse model. We combine simultaneous inhibition of cysteine uptake and transsulfuration in xenograft model using SK-N-DZ cell line. We treated the mice with IKE and PPG together with genetic targeting of GPX4 activity. At the end of the treatment, transcriptional profiling of residual small tumors revealed induction of ferroptosis markers after combined inhibition of cystine uptake/cysteine synthesis and GPX4 as compared to tumors treated with vehicle control.
2022-01-05 | GSE192976 | GEO
Project description:Immune checkpoint blockade is a powerful oncologic treatment modality for a wide variety of human malignancies. Randomized clinical trials are assessing how best to interdigitate this treatment modality with traditional therapies including radiotherapy. A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities including radiotherapy. Here, we demonstrate that radiotherapy induces tumor cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor cell ferroptosis. Mechanistically, IFN derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently, yet synergistically repress SLC7A11, a unit of the glutamate-cystine antiporter xc-, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy.
2020-09-23 | GSE137946 | GEO
Project description:Aberrant glycosylation involves multifaceted pathological and pathophysiological changes in pancreatic ductal adenocarcinoma (PDAC), including but not limited to conferring tumor cells the ability to resist cell death. Ferroptosis driven by lethal lipid peroxidation provides a targetable vulnerability to PDAC. However, the crosstalk between glycosylation and ferroptosis remains unclear. Here, we identified 4F2hc, a subunit of the glutamate-cystine antiporter system Xc–, its N-glycosylation is involved in PDAC ferroptosis by N- and O-linked glycoproteomics. Knockdown of SLC3A2 (gene name of 4F2hc) or blocking the N-glycosylation of 4F2hc potentiates ferroptosis sensitization of PDAC cells by impairing the activity of system Xc– manifested by a marked decrease in intracellular glutathione. To identify which glycosyltransferases are critical for glycosylation initiation during ferroptosis execution. We collected 207 glycosyltransferase genes (GTGs) and performed parallel RNA-seq to reveal that the glycosyltransferase B3GNT3 catalyzes the glycosylation of 4F2hc, which stabilizes the 4F2hc protein as well as its interaction with xCT. Additionally, upon the combination with a ferroptosis inducer, treatment with the classical N-glycosylation inhibitor tunicamycin (TM) markedly triggered the overactivation of lipid peroxidation and enhanced the sensitivity of PDAC cells to ferroptosis. Notably, we confirmed that genetic perturbation of SLC3A2 or combination treatment with TM markedly increased ferroptosis sensitivity in the orthotopic PDAC model. Clinically, high expression of 4F2hc and B3GNT3 contributes to the progression and poor survival of PDAC patients. Collectively, our findings reveal a previously unappreciated function of N-glycosylation of 4F2hc in ferroptosis and suggest that targeting glycosylated 4F2hc can induce susceptibility to ferroptosis in PDAC.
2023-07-12 | GSE207741 | GEO
Project description:Overexpression of MYC family members is linked to poor clinical outcome in many human cancers. These oncoproteins drive proliferation, alter metabolism, and mediate an antioxidant response to maintain tumor cell redox balance. However, to date, there are no effective inhibitors that specifically target MYC-amplified tumors. We demonstrate that MYCN-amplified, aggressive childhood neuroblastoma cells undergo ferroptotic cell death in vivo in the absence of intracellular cysteine, thus implicating MYCN as a predictive biomarker for ferroptosis sensitivity in neuroblastoma. Although cysteine is provided by both uptake from the microenvironment and MYCN-induced transsulfuration of methionine, glutathione levels remain low in these highly proliferative cancer cells due to concomitant cysteine utilization for protein and nucleotide synthesis. Consequently, MYCN-amplified neuroblastoma cells are highly susceptible to lipid peroxidation and ferroptosis, which must be counteracted by GPX4 activity. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. Our data show that MYCN-amplified neuroblastoma is sensitized to ferroptosis, which can be exploited therapeutically, by depleting the intracellular cysteine pool with concomitant GPX4 inactivation. These findings may help to develop novel clinical strategies to target MYCN-amplified tumors by inducing ferroptotic cell death.
2022-01-18 | GSE189174 | GEO