Pancreatic acinar cell fate relies on system xc- to prevent ferroptosis during stress
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ABSTRACT:
PROVIDER: PRJNA1002284 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25525553.fastq.gz | Fastqsanger.gz | |||
| SRR25525554.fastq.gz | Fastqsanger.gz | |||
| SRR25525555.fastq.gz | Fastqsanger.gz | |||
| SRR25525556.fastq.gz | Fastqsanger.gz | |||
| SRR25525557.fastq.gz | Fastqsanger.gz |
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Project description:Acinar cell dedifferentiation is one of the most notable features of acute and chronic pancreatitis. It can also be the initial step that facilitates pancreatic cancer development. In the present study, we further decipher the precise mechanism and regulation using murine experimental models. Our RNAseq analysis indicates that, early acinar cell dedifferentiation is accompanied by multiple pathways related to cell survival that are highly enriched, and where SLC7A11 (xCT) is transiently upregulated. xCT is the specific subunit of the cystine/glutamate antiporter system xC-. Acinar cells with depleted or reduced xCT function show an increase in ferroptosis relating to lipid peroxidation. Lower glutathione levels and more lipid ROS accumulation could be rescued by the antioxidant N-acetylcysteine or the ferroptosis inhibitor Ferrostatin-1. In caerulein-induced acute pancreatitis in mice, xCT also prevents lipid peroxidation in acinar cells. In conclusion, during stress, acinar cell fate seems to be poised for avoiding several forms of cell death. xCT specifically prevents acinar cell ferroptosis by fueling the glutathione pool and maintaining ROS balance. The data suggest that xCT offers a druggable tipping point to steer the acinar cell fate in stress conditions.
2023-08-07 | GSE240106 | GEO
Project description:Acinar cell dedifferentiation is one of the most notable features of acute and chronic pancreatitis. It can also be the initial step that facilitates pancreatic cancer development. In the present study, we further decipher the precise mechanisms and regulation using primary human cells and murine experimental models. Our RNAseq analysis indicates that, in both species, early acinar cell dedifferentiation is accompanied by multiple pathways related to cell survival that are highly enriched, and where SLC7A11 (xCT) is transiently upregulated. xCT is the specific subunit of the cystine/glutamate antiporter system xC-. To decipher its role, gene silencing, pharmacological inhibition and a knock-out mouse model were used. Acinar cells with depleted or reduced xCT function show an increase in ferroptosis relating to lipid peroxidation. Lower glutathione levels and more lipid ROS accumulation could be rescued by the antioxidant N-acetylcysteine or the ferroptosis inhibitor ferrostatin-1. In caerulein-induced acute pancreatitis in mice, xCT also prevents lipid peroxidation in acinar cells. In conclusion, during stress, acinar cell fate seems to be poised for avoiding several forms of cell death. xCT specifically prevents acinar cell ferroptosis by fueling the glutathione pool and maintaining ROS balance. The data suggest that xCT offers a druggable tipping point to steer the acinar cell fate in stress conditions.
| S-EPMC10442358 | biostudies-literature
Project description:Erastin is a small molecular compound which inhibits the system Xc- and prevents the import of cystine, reducing glutathione (GSH) biosynthesis and glutathione peroxidase 4 (GPX4) activity, and finally inducing cell death via ferroptosis. To establish a model of Erastin induced ferroptosis in glioma cells, U87 cells were treated of Erastin (10 μM, 72 h). Combination analysis of HiChIP, ChIP-seq and RNA-seq data suggests that change of chromatin loops mediated by 3D chromatin structure regulate gene expressions in glioma ferroptosis. Genes that regulated by 3D chromatin structure include genes that were reported function in ferroptosis like MDM2 and TXRND1. We propose a new regulatory mechanism governing glioma cell ferroptosis by 3D chromatin structure.
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Project description:Gamma interferon (IFN-γ) was reported to exhibit anti-tumor effects via inducing ferroptosis. Based on genome-wide CRISPR/Cas9 knockout screens, we discovered that cAMP response ele-ment binding protein (CREB) regulated transcription coactivator3 (CRTC3) protects tumor cells from drug induced ferroptosiis and is a significant resister of IFN-γ treatment in hepatocellular car-cinoma (HCC). Mechanically, CRTC3 knockout alters tumor cell lipid pattern and increases the abundance of polyunsaturated fatty acids (PUFAs), which facilitates lipid peroxidation and renders HCC cells susceptible to ferroptosis inducers. To scavenge accumulated lipid peroxides (LPO) and maintain redox equilibrium, HCC cells upregulate SLC7A11 expression to enhance the activity of glutamate-cystine antiporter (system xc-). As IFN-γ inhibiting system xc-, simultaneously treatment of IFN-γ disrupts the compensatory mechanism, and generates a synergistic effect with CRTC3 knockout to facilitate ferroptosis. The sensitizing effect of CRTC3 depletion was further confirmed in typical ferroptosis inducers including RSL3, Erastin and Sorafeinib. Here, we reported a hitherto unexpected role of CRTC3 in regulating PUFAs metabolism and ferroptosis. Targeting the CRTC3 signaling in combination with ferroptosis inducers may represent a viable approach to treat cancer and overcome drug resistance in HCC.
2025-06-24 | GSE206906 | GEO
Project description:Gamma interferon (IFN-γ) was reported to exhibit anti-tumor effects via inducing ferroptosis. Based on genome-wide CRISPR/Cas9 knockout screens, we discovered that cAMP response ele-ment binding protein (CREB) regulated transcription coactivator3 (CRTC3) protects tumor cells from drug induced ferroptosiis and is a significant resister of IFN-γ treatment in hepatocellular car-cinoma (HCC). Mechanically, CRTC3 knockout alters tumor cell lipid pattern and increases the abundance of polyunsaturated fatty acids (PUFAs), which facilitates lipid peroxidation and renders HCC cells susceptible to ferroptosis inducers. To scavenge accumulated lipid peroxides (LPO) and maintain redox equilibrium, HCC cells upregulate SLC7A11 expression to enhance the activity of glutamate-cystine antiporter (system xc-). As IFN-γ inhibiting system xc-, simultaneously treatment of IFN-γ disrupts the compensatory mechanism, and generates a synergistic effect with CRTC3 knockout to facilitate ferroptosis. The sensitizing effect of CRTC3 depletion was further confirmed in typical ferroptosis inducers including RSL3, Erastin and Sorafeinib. Here, we reported a hitherto unexpected role of CRTC3 in regulating PUFAs metabolism and ferroptosis. Targeting the CRTC3 signaling in combination with ferroptosis inducers may represent a viable approach to treat cancer and overcome drug resistance in HCC.
2025-06-24 | GSE206905 | GEO
Project description:Microarray analyses of sweet orange leaves infiltrated with Xc in the presence or absence of Ch, or Ch alone This experiment was used to identify genes up-regulated by Xc independently of protein synthesis Citrus leaves were infiltrated with a suspension of Xc with or without Ch, and mRNA was extrated and processed 8h post inoculation (8hpi)
2014-01-10 | E-GEOD-51367 | biostudies-arrayexpress
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.
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Project description:Anti-PD-1 immunotherapy has been established to be greatly effective in melanoma treatment, but the low response rate and occurrence of treatment resistance significantly hinder its efficacy. Recent studies have demonstrated that IFN-γ secreted by tumor-infiltrating CD8+T cells suppresses the expression of Xc- system to induce ferroptosis of tumor cells. However, whether the escape of tumor cells from ferroptosis facilitates the resistance to immunotherapy and the upstream regulatory mechanism remain elusive. MiRNAs participate in ferroptosis execution and can be delivered systemically by nanoparticle or alternative carriers, through which obvious therapeutic effect on cancer has been obtained. Herein, through RNA sequencing, we first obtained miRNAs expression profile of melanoma cells in IFN-γ-potentiated ferroptosis.
2022-06-29 | GSE186497 | GEO
Project description:Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis
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Project description:Characterized by lethal iron accumulation and lipid peroxidation, ferroptosis plays critical roles in liver injury, especially caused by ischemia/reperfusion (I/R) of hepatic inflow occlusion during liver operation. However, the lack of effective and safe clinical precautionary measure is still the main problem in preventing hepatic ferroptosis. Here, we found that the excessive production of reactive oxygen species could decrease the expression of Interferon (IFN)-stimulated gene DExH-box helicase 58 (DHX58) in hepatocytes, and then promote hepatic ferroptosis, while pre-treatment using IFN-α increased DHX58 expression and prevented ferroptosis during I/R injury. Mechanistically, DHX58 with RNA-binding activity could constitutively associate the mRNA of glutathione peroxidase 4 (GPX4), a crucial ferroptosis suppressor, and then recruit the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in m6A-dependent manner, thus enhancing GPX4 protein level and preventing hepatic ferroptosis. Therefore, we provide mechanistic evidence for the IFN-stimulated DHX58 in promoting the translation of m6A-modified Gpx4 mRNA, and suggest the promising clinical potential of IFN-α pre-treatment in the prevention of hepatic ferroptosis.
2024-05-24 | PXD042083 | Pride