Labile Iron Release Primes Pancreatic Cancer for Ferroptosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA662926 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12624085_1.fastq.gz | Fastqsanger.gz | |||
| SRR12624085_2.fastq.gz | Fastqsanger.gz | |||
| SRR12624086_1.fastq.gz | Fastqsanger.gz | |||
| SRR12624086_2.fastq.gz | Fastqsanger.gz | |||
| SRR12624087_1.fastq.gz | Fastqsanger.gz |
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Project description:Cancers have unique metabolic adaptations in response to cell-intrinsic and environmental stressors, where identifying new strategies to target these adaptions is an area of active research. We previously described a dependency on a cytosolic aspartate aminotransaminase (GOT1)-dependent pathway for NADPH generation in pancreatic cancer. Here, we sought to identify metabolic dependencies following GOT1 inhibition to provide insight into the regulation of redox metabolism. Using pharmacological methods, we identified cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. Targeting any of these pathways triggered ferroptosis, an oxidative, non-apoptotic, iron-dependent form of cell death in GOT1 knockdown cells. Mechanistically, GOT1 inhibition promoted a catabolic state and enhanced the availability of labile iron through autophagy and iron uptake. In sum, our study identifies a novel biochemical connection between GOT1, iron regulation, and ferroptosis, and suggests GOT1 plays a role in protecting PDA from metabolic stress.
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Project description:Polyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells. Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines function as endogenous buffers of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis. Using genome-wide CRISPR screens, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, GPX4. Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin. To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron. Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution. These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance.
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Project description:Polyamines buffer labile iron to suppress ferroptosis
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Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscle disease caused by expression of the transcription factor DUX4, which we previously found to be associated with plasma membrane (PM) repair deficits. However, the molecular mechanisms associated with poor membrane repair are not clear. Here, we show PM injury itself results in mild but significant increase in DUX4 mRNA expression, as well dysregulation of genes enriched in pathways critical for membrane repair. We find these dysregulated genes to be sensitive classifiers of FSHD status in human muscle biopsies, indicating their potential utility as novel biomarkers. In addition, FSHD myoblasts show dysregulation of genes in the ferroptosis cell death signaling pathway in response to membrane damage. Subsequent experiments indicated FSHD myoblasts present with hallmark features of ferroptotic stress, including elevated labile ferrous (Fe2+) iron, and lipid peroxidation at baseline and post-injury. Furthermore, we demonstrate that the expression of ferroptosis biomarkers is elevated in FSHD muscle biopsies, which is predictive of the presence of inflammation and positively correlates with the degree of fatty infiltration in FSHD skeletal muscle. Increasing labile iron and lipid peroxidation worsens membrane repair in FSHD myoblasts, while treatment with the iron chelator 2,2′-Bipyridyl and ferroptosis inhibitor ferrostatin-1 improve repair. These data are the first to identify signs of ferroptotic stress in FSHD myoblasts, and demonstrate the potential therapeutic benefit of iron chelation and ferroptosis inhibition to improve membrane repair capacity in FSHD.
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Project description:Liver iron overload can induce hepatic expression of hepcidin and regulates iron metabolism. However, the mechanism of iron regulating iron metabolism remains known. Intracellular labile iron represents the nonferritin-bound, redox-active iron which is transitory and serves as a crossroad of cell iron metabolism. The role of intracellular labile iron played in iron metabolism has largely been elucidated. Here we show that intracellular labile iron of hepatocytes has dual function in iron metabolism. It can induce hepatocytes expressing hepcidin via ER stress induced transcription factors on the one hand, on the other hand stimulate BMP2 and BMP6 expression of liver sinusoidal endothelial cells (LSECs) though TNFα secreted by hepatocytes to further regulate iron metabolism. Blockade of TNFα could dysregulate the iron metabolism during iron overload. Our findings reveal the important role of intracellular labile iron in iron metabolism and represent a novel way to modulate iron metabolism during iron overload.
2023-05-03 | GSE186655 | GEO
Project description:Despite centuries of research, metastatic cancer remains incurable due to resistance against all conventional cancer therapeutics. Alternative strategies leveraging non-proliferative vulnerabilities in cancer are required to overcome cancer recurrence. Ferroptosis is an iron dependent cell death pathway that has shown promising pre-clinical activity in several contexts of therapeutic resistant cancer. However, ferroptosis sensitivity is highly variable across tissue types and cell state posing a challenge for clinical translation. We describe a convergent phenotype induced by chemotherapy where cells surviving chemotherapy have similar transcriptomic signatures and dysregulated iron homeostasis, regardless of initial cell type or chemotherapy used. Elevated labile iron levels are counteracted by NRF2 signaling that does not alleviate the amount of labile iron. Selectively inhibiting GPX4 leads to uniform susceptibility to ferroptosis in surviving cells, highlighting the common reliance on lipid peroxidation defenses. Cellular iron dysregulation is a vulnerability of chemoresistant cancer cells that can be leveraged by triggering ferroptosis
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Project description:In this study we show that cAMP helps regulate cytosine demethylation through augmenting the intracellular labile ferrous iron pool.
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Project description:Ferroptosis is a unique iron-dependent form of non-apoptotic cell death characterized by devastating lipid peroxidation. Whilst growing evidence suggests that ferroptosis is a type of autophagy-dependent cell death, the underlying molecular mechanisms regulating ferroptosis are largely unknown. In this study, through an unbiased RNA-sequencing screening, we demonstrate the activation of a multi-faceted tumor-suppressor protein Par-4/PAWR during ferroptosis. Functional studies reveal that genetic depletion of Par-4 effectively blocks ferroptosis, whereas Par-4 overexpression sensitizes cells to undergo ferroptosis. More importantly, we have determined that Par-4-triggered ferroptosis is mechanistically driven by the autophagic machinery. Upregulation of Par-4 promotes activation of ferritinophagy (autophagic degradation of ferritin) via the nuclear receptor co-activator 4 (NCOA4), resulting in excessive release of free labile iron and, hence, enhanced lipid peroxidation and ferroptosis. Inhibition of Par-4 dramatically suppresses the NCOA4-mediated ferritinophagy signaling axis. Our results also establish that Par-4 activation positively correlates with reactive oxygen species (ROS) production, which is critical for ferritinophagy-mediated ferroptosis. Furthermore, Par-4 knockdown effectively blocked ferroptosis-mediated tumor suppression in the mouse xenograft models. Collectively, these findings reveal that Par-4 has a crucial role in ferroptosis, which could be further exploited for cancer therapy.
2024-05-24 | GSE267823 | GEO
Project description:Intracellular labile iron is a key regulator of hepcidin expression and iron metabolism
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Project description:Ferroptosis is a regulated form of necrotic cell death caused by an iron-dependent accumulation of oxidized phospholipids in cellular membranes, which culminates in plasma membrane rupture (PMR) and cell lysis. PMR is also a hallmark of other types of programmed necrosis, such as pyroptosis and necroptosis, where it is initiated by dedicated pore-forming cell death executors. Yet, whether ferroptosis-associated PMR is actively executed by a protein or driven by osmotic pressure remains unknown. Here, we investigated the role of ninjurin-1 (NINJ1), the recently identified executor of pyroptosis-associated PMR, in ferroptosis. We report that during ferroptosis NINJ1 oligomerizes and that Ninj1-deficiency protects macrophages and fibroblasts from ferroptosis-associated PMR. Mechanistically, we find that NINJ1 is dispensable for the early steps of ferroptosis, such as lipid peroxidation, channel-mediated calcium influx and cell swelling. By contrast, NINJ1 is required for early loss of plasma membrane integrity, an event that precedes complete PMR. Furthermore, NINJ1 mediates the release of cytosolic proteins and danger-associated molecular patterns (DAMPs) from ferroptotic cells, suggesting that targeting NINJ1 could be a therapeutic option to reduce ferroptosis-associated inflammation.
2024-02-15 | PXD047622 | Pride