IFI16-mediated cellular senescence drives HMOX1-dependent evasion of ferroptosis and radioresistance in glioblastoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1144925 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30148164_1.fastq.gz | Fastqsanger.gz | |||
| SRR30148164_2.fastq.gz | Fastqsanger.gz | |||
| SRR30148165_1.fastq.gz | Fastqsanger.gz | |||
| SRR30148165_2.fastq.gz | Fastqsanger.gz | |||
| SRR30148166_1.fastq.gz | Fastqsanger.gz |
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Project description:Glioblastoma multiforme (GBM) remains a therapeutic challenge due to its aggressive nature and recurrence. This study establishes a radioresistant GBM cell model through repeated irradiation and observes a cellular senescence-like phenotype in these cells. Comprehensive genomic and transcriptomic analyses identify IFI16 as a central regulator of this phenotype and contributes to radioresistance. IFI16 activates HMOX1 transcription thereby attenuating ferroptosis by reducing lipid peroxidation, ROS production, and intracellular Fe2+ content following irradiation. Furthermore, IFI16 interacts with the transcription factors JUND and SP1 through its pyrin domain, robustly facilitating HMOX1 expression, further inhibiting ferroptosis and enhancing radioresistance in GBM. Notably, glyburide, a sulfonylurea compound, effectively disrupts IFI16 function and enhances ferroptosis and radiosensitivity. By targeting the pyrin domain of IFI16, glyburide emerges as a potential therapeutic agent against GBM radioresistance. These findings underscore the central role of IFI16 in GBM radioresistance and offer promising avenues to improve GBM treatment.
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Project description:Osteocytes are the main cells in mineralized bone tissue. Elevated osteocyte apoptosis has been observed in lytic bone lesions of patients with multiple myeloma. However, their precise contribution to bone metastasis remains unclear.Here, we investigated the pathogenic mechanisms driving melanoma-induced osteocyte death. Both in vivo models and in vitro assays were combined with untargeted RNA sequencing approaches to explore the pathways governing melanoma-induced osteocyte death. We could show that ferroptosis is the primary mechanism behind osteocyte death in the context of melanoma bone metastasis. HMOX1 was identified as a crucial regulatory factor in this process, directly involved in inducing ferroptosis and affecting osteocyte viability. We uncover a non-canonical pathway that involves excessive autophagy-mediated ferritin degradation, highlighting the complex relationship between autophagy and ferroptosis in melanoma-induced osteocyte death. In addition, HIF1α pathway was shown as an upstream regulator, providing a potential target for modulating HMOX1 expression and influencing autophagy-dependent ferroptosis. In conclusion, our study provides insight into the pathogenic mechanisms of osteocyte death induced by melanoma bone metastasis, with a specific focus on ferroptosis and its regulation. This would enhance our comprehension of melanoma-induced osteocyte death.
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Project description:Ferroptosis, an iron-dependent, non-apoptotic cell death program, is involved in a variety of degenerative diseases and represents a targetable vulnerability in certain cancers. The ferroptosis-susceptible cell-state can either preexist in cells arising from certain lineages or be acquired during cell-state transitions. Precisely how ferroptosis susceptibility is dynamically regulated remains poorly understood. Using genome-wide CRISPR/Cas9 suppressor screens, we identify a key role for peroxisome–ether phospholipid genes in driving ferroptosis susceptibility and evasion in ovarian cancer.
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Project description:Myeloid-derived suppressor cells (MDSCs) are immune suppressive cells that massively accumulate under pathological conditions to suppress T cell immune response. Dysregulated cell death contributes to MDSC accumulation, but the molecular mechanism underlying this cell death dysregulation is not fully understood. We report here that neutral ceramidase (N-acylsphingosine amidohydrolase, ASAH2) is highly expressed in tumor-infiltrating MDSCs in colon carcinoma and acts as a MDSC survival factor. To target ASAH2, we performed molecular docking based on human ASAH2 protein structure. Enzymatic inhibition analysis of identified hits determined NC06 as an ASAH2 inhibitor. Chemical and NMR analysis determined NC06 as 7-chloro-2-(3-chloroanilino)pyrano[3,4-e][1,3]oxazine-4,5-dione. NC06 inhibits ceramidase activity with IC50 of 10.16-25.91 M for human ASAH2 and 18.6-30.2 uM for mouse Asah2 proteins. NC06 induces MDSC death in a dose-dependent manner and inhibition of ferroptosis decreased NC06-induced MDSC death. NC06 increases glutathione synthesis and decrease lipid ROS to suppress ferroptosis in MDSCs. Gene expression profiling identified p53 pathway as the Asah2 target in MDSCs. Inhibition of Asah2 increased p53 protein stability to up-regulate Hmox1 expression to suppress lipid ROS production to suppress ferroptosis in MDSCs. NC06 therapy increases MDSC death and reduces MDSC accumulation in tumor-bearing mice, resulting in increased activation of tumor-infiltrating CTLs and suppression of tumor growth in vivo. Our data indicate that ASAH2 protects MDSCs from ferroptosis through destabilizing p53 protein to suppress the p53 pathway in MDSCs in the tumor microenvironment. Targeting ASAH2 with NC06 to induce MDSC ferroptosis is potentially an effective therapy to suppress MDSC accumulation in cancer immunotherapy.
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