TFCP2L1 promotes GPX4-mediated ferroptosis to inhibit breast cancer cell proliferation and metastasis via the PI3K/AKT signaling pathway
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PROVIDER: PRJNA1127507 | ENA |
REPOSITORIES: ENA
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Project description:Breast cancer represents the most prevalent form of malignant tumors among women. Despite the existence of numerous therapeutic methods, a significant portion of patients face a poor prognosis, highlighting the urgency in identifying new remedial targets. Here, we for the first time demonstrated that the CP2 family member TFCP2L1, a classical marker of embryonic stem cell maintenance, as a tumor suppressor in breast cancer. Patients with breast cancer have poorer prognoses when TFCP2L1 is expressed highly. Consistently, the expression of TFCP2L1 is higher in normal breast cells than those in breast cancer cell lines. Gain- and loss-of-function and xenograft tumor assay showed that overexpression of TFCP2L1 significantly inhibited both the proliferation and migration of breast cancer cells in vivo and in vitro. Conversely, the knockdown of TFCP2L1 promoted the proliferation and migration of breast cancer cells. Mechanistically, we found that TFCP2L1 suppresses breast cancer progression by directly inhibiting the expression of glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis. Therefore, inhibition of GPX4 by RSL3, an inducer of ferroptosis was able to promote the function of TFCP2L1 in breast cancer cells. On the other hand, transcriptome high-throughput exhibited that TFCP2L1 negatively regulated the activity of PI3K/AKT signaling pathway. Administration of SC79, an AKT activator, was capable of partially restoring the negative effects of TFCP2L1 on GPX4 transcription. Together, TFCP2L1 functions by directly or indirectly regulating GPX4-mediated ferroptosis, and may serve as a novel biomarker and potential therapeutic target for breast cancer.
2024-07-30 | GSE270578 | 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:Invariant natural killer T (iNKT) cells are a group of innate like T cells that plays important roles in immune homeostasis and activation. We found that iNKT cells, compared to CD4+ T cells, have significantly higher levels of lipid peroxidation in both mice and humans. Proteomic analysis also demonstrated that iNKT cells express higher levels of Glutathione peroxidase 4 (Gpx4), a major antioxidant enzyme that reduces lipid peroxidation and prevents ferroptosis. T cell specific deletion of Gpx4 reduces iNKT cell population, most prominently the IFNg producing NKT1 subset. RNAseq analysis revealed IFNg signaling, cell cycle regulation, as well as mitochondrial function are perturbed by Gpx4 deletion in iNKT cells. Consistently, we detected impaired cytokine production, elevated cell proliferation and cell death, and accumulation of lipid peroxides and mitochondrial ROS in Gpx4 KO iNKT cells. Ferroptosis inhibitor, iron chelator, vitamin E and vitamin K2 can prevent ferroptosis induced by Gpx4 deficiency in iNKT cells and ameliorate the impaired function of iNKT cells due to Gpx4 inhibition. Lastly, vitamin E rescued iNKT cell population in Gpx4 KO mice. Altogether, our findings reveal the critical role of Gpx4 in regulating iNKT cell homeostasis and function, through controlling lipid peroxidation and ferroptosis.
2024-08-20 | GSE270485 | GEO
Project description:Background: Intestinal failure-associated liver disease (IFALD) is a common complication of long-term parenteral nutrition (PN) that is associated with significant morbidity and mortality. Ferroptosis, as an iron-dependent regulated cell death, has been shown to play an important role in the development of several liver diseases. This study focuses on investigating whether the ferroptosis phenomenon is present in TPN-induced IFALD and further exploring the potential regulatory mechanisms. Methods: Ferroptosis hallmarkers were measured in children with short bowel syndrome (SBS) who had long-term PN use and caused IFALD. Sprague-Dawley (SD) rats were used to establish a rat model of IFALD with a concomitant ferroptosis inhibition intervention using liproxstain-1. The mir-431 lineage was identified as a potential upstream regulatory mir-RNA by mir-RNA sequencing. HepG2 and 293T cell line was used to demonstrate that mir-431 regulates ferroptosis through the GPX4 pathway at the cellular level in vitro. Results: Ferroptosis is upregulated in liver of children with IFALD. Liproxstain-1 downregulates ferroptosis in a rat model of IFALD and attenuates hepatic steatosis through the lipid metabolism pathway. In vitro HepG2 and 293T cell experiments reveal that mir-431 affects ferroptosis by regulating GPX4 protein. Conclusions: Ferroptosis plays an important role in the development of IFALD. Liproxstain-1 inhibits ferroptosis and attenuates hepatic steatosis in a rat model of IFALD through the lipid metabolism pathway. Mir-431 negatively regulates GPX4 protein-induced ferroptosis.
2024-01-01 | GSE223895 | GEO
Project description:Purpose: Identification of Gpx4-dependent genes in resting and activated Treg cells Methods: RNA was purified from resting of stimulated (aCD3-CD38 for 4 h) splenic Treg cells sorted from WT or Foxp3CreGpx4fl/fl mice Conclusions: Gpx4 prevents lipid peroxidation and ferroptosis of activated Treg cells..
2021-10-31 | GSE160338 | GEO
Project description:We have used in vivo selection to isolate GPX4 knockout 786-O cells that have evaded ferroptosis in vivo in mouse xenograft experiments. RNA-seq and Exome-seq profiling were performed to characterize the mechanisms underlying ferroptosis evasion in these in vivo-derived ferroptosis resistant cells.
2020-09-16 | GSE148297 | GEO
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:Background: Autologous fat grafting is hampered by unpredictable graft survival, which is potentially regulated by ferroptosis. Glutathione (GSH), a powerful antioxidant used in tissue preservation, has ferroptosis-regulating activity; however, its effects on fat grafts are unclear. This study investigated the effects and mechanisms of GSH in fat graft survival. Methods: Human lipoaspirates were transplanted subcutaneously into the backs of normal saline-treated (control) or GSH-treated nude mice. Graft survival was evaluated by magnetic resonance imaging and histology. RNA sequencing was performed to identify differentially expressed genes and enriched pathways. GSH activity was evaluated in vitro using an oxygen and glucose deprivation (OGD) model of adipose-derived stem cells. Results: Compared with control group, GSH induced better outcomes, including superior graft retention, appearance, and histological structures. RNA sequencing suggested enhanced negative regulation of ferroptosis in the GSH-treated grafts, which showed reduced lipid peroxides, better mitochondrial ultrastructure, and SLC7A11/GPX4 axis activation. In vitro, OGD-induced ferroptosis was ameliorated by GSH, which restored cell proliferation, reduced oxidative stress, and upregulated ferroptosis defense factors. Conclusions: Our study confirms that ferroptosis participates in regulating fat graft survival and that GSH exerts a protective effect by inhibiting ferroptosis. GSH-assisted lipotransfer is a promising therapeutic strategy for future clinical application.
2023-05-08 | GSE231511 | GEO
Project description:Glioma cells hijack developmental transcriptional programs to control cell state. During neural development, lineage trajectories rely on specialized metabolic pathways. However, the link between tumor cell state and metabolic programs is poorly understood in glioma. Here we uncover a glioma cell state-specific metabolic liability that can be leveraged therapeutically. To model the diversity of glioma cell states, we generated genetically-engineered murine gliomas, induced by deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling CNS cell fate. N1IC tumors harbored quiescent astrocyte-like transformed cell states while p53 tumors were comprised of proliferating progenitor-like cell states. N1IC cells exhibit distinct metabolic alterations, with mitochondrial uncoupling and increased ROS production rendering them more sensitive to inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Importantly, treating patient-derived organotypic slices with a GPX4 inhibitor induced selective depletion of quiescent AC-like glioma cell populations with similar metabolic profiles.
2023-08-16 | GSE224727 | GEO
Project description:Knockout or inhibition of glutathione peroxidase 4 (GPX4) induces ferroptosis which has been proposed as a potential therapeutic strategy for cancer. Here we unexpectedly found that inducible knockout of GPX4 in tumor cells significantly promotes non-small cell lung cancer (NSCLC) progression in the autochthonous KrasLSL-G12D/+Lkb1fl/fl (KL) and KrasLSL-G12D/+Tp53fl/fl (KP) mouse models, whereas inducible overexpression of GPX4 in tumor cells had an opposite effect. Mechanistically, knockout of GPX4 in tumor cells results in the accumulation of triacylglycerol (TAG) that was stored in lipid droplets in tumor cells and the efflux of TAG that induces ferroptosis of macrophages in the tumor microenvironment (TME), thereby igniting an immunoinhibitory TME characterized by the dysfunction of anti-tumor T cells and the decrease of antigen-presenting macrophages. Consistently, treatment with liprostatin-1 or inducible overexpression of GPX4 in tumor cells significantly rescues the ferroptosis of macrophages and ignites the activation of T cells in the TME, thereby inhibiting NSCLC progression. These findings highlight a previously uncharacterized role of tumor cell-specific GPX4 in NSCLC progression by modulating TAG metabolism in the TME and provide potential therapeutic strategies for NSCLC.
2024-11-05 | GSE281159 | GEO