Effects of ferroptosis inducer FIN56 in HSC-3 HNSCC cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA807951 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18058060.fastq.gz | Fastqsanger.gz | |||
| SRR18058061.fastq.gz | Fastqsanger.gz |
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Project description:We treated ferroptosis inducer FIN56 (1uM,48hrs) in HSC-3 HNSCC cells. DMSO treatment as control cells group.
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Project description:Cancers coopt stress-response pathways to drive oncogenesis, dodge immune surveillance, and resist cytotoxic therapies. Several of these provide protection from ferroptosis, iron-mediated oxidative cell death. Here, we found dramatic sensitization to ferroptosis upon disruption of cap-dependent translation in diffuse large B-cell lymphoma (DLBCL). Specifically, rocaglate inhibitors of the eIF4A1 RNA helicase synergized with pharmacologic ferroptosis inducers, driven by a collapse of glutathione production that protects polyunsaturated fatty acids from ferroptotic oxidation. These effects occur despite initial up-regulation of specific protective factors. We find lost translation of NRF2, oncogenic master regulator of antioxidant gene-expression, is a key consequence of eIF4A1 inhibition. In vivo, combination of the clinical rocaglate zotatifin with a pharmacologically optimized ferroptosis inducer eradicated DLBCL patient derived xenografts. Moreover, we found zotatifin pre-exposure sensitized DLBCL to CD19-directed chimeric antigen receptor (CAR-19) T cells. Translational disruption therefore provides new opportunities to leverage therapeutic impacts of ferroptosis inducers including cytotoxic immunotherapies.
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Project description:Ferroptosis, a non-apoptotic programmed cell death triggered by excessive iron-dependent lipid peroxidation, plays a pivotal role in tumor progression. Significant progress has been made in elucidating the role of transcription factors in the regulation of ferroptosis. Nevertheless, the identification of the key transcription factor responsible for inducing ferroptosis remains elusive. In this study, we discovered that ATOH8 is upregulated in prostate cancer cells treated with the ferroptosis inducer. Overexpression of ATOH8 increased the vulnerability of prostate cancer to ferroptosis, while ATOH8 deletion promotes ferroptosis evasion. Mechanistically, ATOH8 suppresses the transcription of SCD, reducing the synthesis of monounsaturated fatty acids that confer resistance to ferroptosis. Additionally, ATOH8 works in conjunction with the E protein E47 to form a transcriptional repression complex that inhibits SCD transcription. Furthermore, we discovered that EZH2 epigenetically suppresses the expression of ATOH8 through DNA methylation and H3K27 methylation. Interestingly, EZH2 was found to be downregulated in ferroptosis, resulting in an upregulation of ATOH8. Pharmacological inhibition of EZH2 combined with ferroptosis inducer significantly suppresses prostate cancer growth in vitro and in vivo. Together, our findings unveil that EZH2-mediated ATOH8 downregulation promotes ferroptosis evasion and suggest that pharmacological manipulation of EZH2 and ATOH8 is a promising therapeutic strategy for prostate cancer.
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Project description:Ferroptosis, a non-apoptotic programmed cell death triggered by excessive iron-dependent lipid peroxidation, plays a pivotal role in tumor progression. Significant progress has been made in elucidating the role of transcription factors in the regulation of ferroptosis. Nevertheless, the identification of the key transcription factor responsible for inducing ferroptosis remains elusive. In this study, we discovered that ATOH8 is upregulated in prostate cancer cells treated with the ferroptosis inducer. Overexpression of ATOH8 increased the vulnerability of prostate cancer to ferroptosis, while ATOH8 deletion promotes ferroptosis evasion. Mechanistically, ATOH8 suppresses the transcription of SCD, reducing the synthesis of monounsaturated fatty acids that confer resistance to ferroptosis. Additionally, ATOH8 works in conjunction with the E protein E47 to form a transcriptional repression complex that inhibits SCD transcription. Furthermore, we discovered that EZH2 epigenetically suppresses the expression of ATOH8 through DNA methylation and H3K27 methylation. Interestingly, EZH2 was found to be downregulated in ferroptosis, resulting in an upregulation of ATOH8. Pharmacological inhibition of EZH2 combined with ferroptosis inducer significantly suppresses prostate cancer growth in vitro and in vivo. Together, our findings unveil that EZH2-mediated ATOH8 downregulation promotes ferroptosis evasion and suggest that pharmacological manipulation of EZH2 and ATOH8 is a promising therapeutic strategy for prostate cancer.
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Project description:Despite the remarkable success of programmed death 1/PD-L1 inhibition in tumor therapy, only a minority of patients benefits from it. Previous studies suggest the anti-PD-1 treatment failure may attribute to the intrinsic functions of PD-L1 in cancer cells. Here, we established a genome-wide CRISPR synthetic lethality screen to systematic explore the PD-L1 intrinsic function in head and neck squamous cell carcinoma (HNSCC) cells. Ferroptosis related genes were identified to be essential for PD-L1 deficient cell viability. Genetic and pharmacological induction of ferroptosis accelerated cell death in PD-L1 knockout cells. PD-L1 knockout cells were also highly susceptible to immunogenic ferroptosis in vitro and in vivo. Mechanistically, nuclear PD-L1 transcriptionally activated SOD2 expression to maintain redox homeostasis. Importantly, the lower ROS and ferroptosis were observed in HNSCC patients with the higher expression of PD-L1. In summary, our study illustrates that PD-L1 confers ferroptosis resistance by activating SOD2-meidated redox homeostasis in HNSCC cells, indicating an enhanced therapeutic effect can be achieved by targeting the intrinsic PD-L1 function during immunotherapy.
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Project description:Despite the remarkable success of programmed death 1/PD-L1 inhibition in tumor therapy, only a minority of patients benefits from it. Previous studies suggest the anti-PD-1 treatment failure may attribute to the intrinsic functions of PD-L1 in cancer cells. Here, we established a genome-wide CRISPR synthetic lethality screen to systematic explore the PD-L1 intrinsic function in head and neck squamous cell carcinoma (HNSCC) cells. Ferroptosis related genes were identified to be essential for PD-L1 deficient cell viability. Genetic and pharmacological induction of ferroptosis accelerated cell death in PD-L1 knockout cells. PD-L1 knockout cells were also highly susceptible to immunogenic ferroptosis in vitro and in vivo. Mechanistically, nuclear PD-L1 transcriptionally activated SOD2 expression to maintain redox homeostasis. Importantly, the lower ROS and ferroptosis were observed in HNSCC patients with the higher expression of PD-L1. In summary, our study illustrates that PD-L1 confers ferroptosis resistance by activating SOD2-meidated redox homeostasis in HNSCC cells, indicating an enhanced therapeutic effect can be achieved by targeting the intrinsic PD-L1 function during immunotherapy.
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Project description:Ferroptosis is a form of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated-fatty-acid-containing phospholipids (PUFA-PLs). Three key molecular features of ferroptosis are peroxidation of PUFA-PLs, accumulation of redox-active ferrous iron, and defective lipid peroxide repair (Dixon and Stockwell, 2019). However, there is currently no reliable way to selectively stain ferroptotic cells in tissue sections to characterize the extent of ferroptosis in animal models of disease and in patient tissue samples. We sought to address this gap by immunizing mice with membranes from lymphoma cells treated with the ferroptosis inducer piperazine erastin (PE), and screening ~4,750 of the resulting monoclonal antibodies generated for their ability to selectively detect cells undergoing ferroptosis. We found that one antibody, termed 3F3 Ferroptotic Membrane Antibody (3F3-FMA), was effective as a selective ferroptosis-staining reagent using immunofluorescence (IF). The antigen of 3F3-FMA was identified by immunoprecipitation and mass spectrometry as the human transferrin receptor 1 protein (TfR1), which imports iron from the extracellular environment into cells. We validated this finding with several additional anti-TfR1 antibodies, and compared them to other potential ferroptosis-detecting reagents via immunofluorescence staining, using fluorescence microscopy and flow cytometry. We found that anti-TfR1 and anti-malondialdehyde (MDA) adduct antibodies were effective at reliably staining ferroptotic tumor cells in numerous cell culture and tissue contexts. In summary, these findings suggest that anti-TfR1 antibodies can be used to selectively label cells undergoing ferroptosis.
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