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.
2023-03-24 | GSE196947 | GEO
Project description:Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, functions as an innate tumor suppression mechanism. However, the regulatory networks governing ferroptosis sensitivity in cancer cells remain incompletely elucidated. In this study, we identify RAB11FIP5 as a novel negative regulator of ferroptosis in head and neck squamous cell carcinoma (HNSCC) cells. Mechanistically, RAB11FIP5 competitively binds to RAB11A against RAB11FIP1, thereby inhibiting the recycling of transferrin (TF) and transferrin receptor (TFR), which are critical for cellular iron import. Furthermore, we demonstrate that USP52 acts as a deubiquitinase that stabilizes RAB11FIP5 by removing the K48 ubiquitin chains in ferroptosis-resistant HNSCC cells. In a subcutaneous xenograft model, knockout of RAB11FIP5 not only enhances the anti-tumor efficacy of the ferroptosis inducer IKE but also suppresses HNSCC tumor growth even in the absence of IKE treatment. Analysis of public databases and patient tissue samples reveals that high RAB11FIP5 expression in HNSCC tumors correlates with poor prognosis. Collectively, our findings elucidate a previously unrecognized mechanism by which RAB11FIP5 regulates ferroptosis through modulating TF/TFR recycling, highlighting its potential as both a prognostic marker and a therapeutic target for HNSCC.
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Project description:Ferroptosis resistance continues to be a major challenge in the treatment of head and neck squamous cell carcinoma (HNSCC), yet the molecular mechanisms driving this resistance remain inadequately understood. Here, we conducted an unbiased genome-wide CRISPR-Cas9 knockout library screen and identified TRAPPC4 as a key protein that resists ferroptosis in HNSCC. Moreover, we conducted experiments using HNSCC cell lines, patient-derived organoids, cell-derived xenograft, patient-derived xenograft, conditional knockout mouse models, and popliteal lymph node and lung metastasis models, which confirmed that TRAPPC4 promotes HNSCC progression by inhibiting ferroptosis. Mechanistically, TRAPPC4 inhibits chromatin accessibility at the TRIM55 promoter, blocking FOS driven TRIM55 transcription, reducing TRIM55-mediated GPX4 degradation, and promoting ferroptosis resistance. We further identified pitavastatin calcium as a TRAPPC4 inhibitor and found that its combination with RSL3 effectively suppressed HNSCC progression. This work reveals the critical role of TRAPPC4-mediated ferroptosis in promoting HNSCC progression and provides a promising therapeutic target for treating HNSCC.
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Project description:Ferroptosis resistance continues to be a major challenge in the treatment of head and neck squamous cell carcinoma (HNSCC), yet the molecular mechanisms driving this resistance remain inadequately understood. Here, we conducted an unbiased genome-wide CRISPR-Cas9 knockout library screen and identified TRAPPC4 as a key protein that resists ferroptosis in HNSCC. Moreover, we conducted experiments using HNSCC cell lines, patient-derived organoids, cell-derived xenograft, patient-derived xenograft, conditional knockout mouse models, and popliteal lymph node and lung metastasis models, which confirmed that TRAPPC4 promotes HNSCC progression by inhibiting ferroptosis. Mechanistically, TRAPPC4 inhibits chromatin accessibility at the TRIM55 promoter, blocking FOS driven TRIM55 transcription, reducing TRIM55-mediated GPX4 degradation, and promoting ferroptosis resistance. We further identified pitavastatin calcium as a TRAPPC4 inhibitor and found that its combination with RSL3 effectively suppressed HNSCC progression. This work reveals the critical role of TRAPPC4-mediated ferroptosis in promoting HNSCC progression and provides a promising therapeutic target for treating HNSCC.
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Project description:Ferroptosis resistance continues to be a major challenge in the treatment of head and neck squamous cell carcinoma (HNSCC), yet the molecular mechanisms driving this resistance remain inadequately understood. Here, we conducted an unbiased genome-wide CRISPR-Cas9 knockout library screen and identified TRAPPC4 as a key protein that resists ferroptosis in HNSCC. Moreover, we conducted experiments using HNSCC cell lines, patient-derived organoids, cell-derived xenograft, patient-derived xenograft, conditional knockout mouse models, and popliteal lymph node and lung metastasis models, which confirmed that TRAPPC4 promotes HNSCC progression by inhibiting ferroptosis. Mechanistically, TRAPPC4 inhibits chromatin accessibility at the TRIM55 promoter, blocking FOS driven TRIM55 transcription, reducing TRIM55-mediated GPX4 degradation, and promoting ferroptosis resistance. We further identified pitavastatin calcium as a TRAPPC4 inhibitor and found that its combination with RSL3 effectively suppressed HNSCC progression. This work reveals the critical role of TRAPPC4-mediated ferroptosis in promoting HNSCC progression and provides a promising therapeutic target for treating HNSCC.
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Project description:Ferroptosis resistance continues to be a major challenge in the treatment of head and neck squamous cell carcinoma (HNSCC), yet the molecular mechanisms driving this resistance remain inadequately understood. Here, we conducted an unbiased genome-wide CRISPR-Cas9 knockout library screen and identified TRAPPC4 as a key protein that resists ferroptosis in HNSCC. Moreover, we conducted experiments using HNSCC cell lines, patient-derived organoids, cell-derived xenograft, patient-derived xenograft, conditional knockout mouse models, and popliteal lymph node and lung metastasis models, which confirmed that TRAPPC4 promotes HNSCC progression by inhibiting ferroptosis. Mechanistically, TRAPPC4 inhibits chromatin accessibility at the TRIM55 promoter, blocking FOS driven TRIM55 transcription, reducing TRIM55-mediated GPX4 degradation, and promoting ferroptosis resistance. We further identified pitavastatin calcium as a TRAPPC4 inhibitor and found that its combination with RSL3 effectively suppressed HNSCC progression. This work reveals the critical role of TRAPPC4-mediated ferroptosis in promoting HNSCC progression and provides a promising therapeutic target for treating HNSCC.
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Project description:Diverse Compounds from Pleuromutilin Lead to a Thioredoxin Inhibitor and Inducer of Ferroptosis
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Project description:Ferroptosis is a unique form of intracellular iron-dependent cell death that differs from apoptosis, necrosis, and autophagy. GPX4, an antioxidant defense enzyme, plays a pivotal role as regulator of ferroptosis. Extensive researches suggest that targeting GPX4 holds promise for cancer therapy. However, the current GPX4 inhibitors face challenges due to unfavorable drug-like properties, which hinder their progress in clinical development. In this study, we identified a novel inhibitor called MI-2, demonstrating potent ferroptosis-inducing capacity. Mechanistically, MI-2 effectively inhibits the activity of GPX4 by direct interaction. Furthermore, MI-2 promotes the degradation of GPX4 through its well-established target, MALT1. In multiple cancer models, MI-2 has demonstrated synergistic effects when combined with sorafenib or regorafenib, resulting in enhanced ferroptosis induction. These findings highlight the dual modulatory effects of MI-2 on GPX4 activity and stability, offering a promising starting point for the development of drug-like GPX4 inhibitors with translational potential.
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Project description:To seek ferroptosis related genes in liver cancer cells, we treated HepG2 cells using ferroptosis inducer Erastin and inhibitor Ferrostatin, respectively. We found that a subset of genes were up-regulated in Erastin treatment groups and down-regulated in Ferrostatin treatment groups, suggesting that these genes might be correlated with ferroptosis.
2019-06-10 | GSE104462 | GEO
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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