Ferroptosis is programmed by the coordinated regulation of glutathione and iron metabolism by BACH1

Nishizawa, Hironari; Matsumoto, Mitsuyo; Shindo, Tomohiko; Saigusa, Daisuke; Kato, Hiroki; Suzuki, Katsushi; Satō, Masaki; Ishii, Yusho; Shimokawa, Hiroaki; Igarashi, Kazuhiko

doi:10.1101/644898

Cited by 5 publications

(7 citation statements)

References 58 publications

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“…Ferrous iron released upon ferritinophagy has been shown to promote ferroptosis (49). Indeed, ferrous iron is increased during the induction of ferroptosis (50). Consistent with these observations, inhibition of ferritinophagy suppresses ferroptosis (51).…”

Section: Discussionmentioning

confidence: 58%

Cysteine restriction induces ferroptosis depending on the polyamine biosynthetic pathway in hepatic cancer cells

Tada,

Nishizawa,

Shima

et al. 2024

Preprint

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Background and Aims: Metabolic activities are also known to affect responses and disease processes of the liver which is a central organ for organismal metabolism. Liver diseases like intestinal failure associated liver disease (IFALD) and hepatocellular carcinoma are known to be affected by nutrition contents but the mechanisms behind remain unclear. In this study, we aimed to investigate the relationship between the concentration of sulfur-containing amino acids and hepatocellular response, and further investigated the mechanism focusing on methionine adenosyltransferase (MAT), which plays a central role in methionine metabolism by synthesizing S-adenosylmethionine (SAM). Methods: Mouse hepatoma Hepa1 cells were cultured in media with reduced amounts of cysteine, methionine, or both. Cell death was monitored using propidium iodide (PI) and annexin V staining followed by flow cytometry. Inhibitors of ferroptosis (Fer-1), autophagy (GSK872), SAM synthesis (cycloleucine), or polyamine synthesis (sardomozide and DFMO) were used. Results: Cysteine restriction induced marked cell death, whereas simultaneous restriction of cysteine and methionine fully suppressed the cell death. Cysteine restriction-induced cell death was suppressed with Fer-1 and GSK872, suggesting the involvement of ferroptosis in this process. Cysteine restriction-induced cell death was also suppressed with knockdown of MAT2A or its inhibitor cycloleucine. Furthermore, inhibitors of several enzymes in the polyamine biosynthetic pathway also suppressed the cell death. In contrast, primary culture of mouse hepatocytes did not show cell death upon cysteine restriction. Conclusions: These results suggest that SAM-polyamine metabolism is a critical modulator of ferroptosis of hepatic cancer cells. Since normal liver cells were more resistant to ferroptosis than cancer cells, cysteine restriction may be exploited in treating hepatic cancer by inducing ferroptosis specifically among cancer cells.

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Section: Discussionmentioning

confidence: 58%

Cysteine restriction induces ferroptosis depending on the polyamine biosynthetic pathway in hepatic cancer cells

Tada,

Nishizawa,

Shima

et al. 2024

Preprint

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“…Such alteration has been shown to be associated with protein misfolding. Possibly, high expression of the translation mediated by labile iron could induce an over translation rate, resulting in less accurate translation which is prone to promote protein misfolding (38,39). On the other hand, labile iron itself was capable of binding with amino acid in peptide chains, resulting in abnormal folding peptides, which could further aggregate to misfolding peptides or proteins (14,15).…”

Section: Resultsmentioning

confidence: 99%

The Role of Labile Iron on Brain Proteostasis; Could it be an Early Event of Neurodegenerative Disease?

Kittilukkana,

Intakhat,

Pilapong

2023

Preprint

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Iron deposits in the brain are a natural consequence of aging. Iron accumulation, especially in the form of labile iron, can trigger a cascade of adverse effects, eventually leading to neurodegeneration and cognitive decline. Aging also increases the dysfunction of cellular proteostasis. The question of whether iron alters proteostasis is now being pondered. Herein, we investigated the effect of ferric citrate, considered as labile iron, on various aspects of proteostasis of neuronal cell lines, and also established an animal model having a labile iron diet in order to evaluate proteostasis alteration in the brain along with behavioral effects. According to anin vitrostudy, labile iron was found to activate lysosome formation but inhibits lysosomal clearance function. Furthermore, the presence of labile iron can alter autophagic flux and can also induce the accumulation of protein aggregates. RNA-sequencing analysis further reveals the upregulation of various terms related to proteostasis along with neurodegenerative disease-related terms. According to an in vivo study, a labile iron-rich diet does not induce iron overload conditions and was not detrimental to the behavior of male Wistar rats. However, an iron-rich diet can promote iron accumulation in a region-dependent manner, particularly in the cortex. By staining for autophagic markers and misfolding proteins in the cerebral cortex, the iron-rich diet was actually found to alter autophagy and induce an accumulation of misfolding proteins. These findings emphasize the importance of labile iron on brain cell proteostasis, which could be implicated in developing of neurological diseases.Graphical abstract

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“…BACH1 is a hemoglobin-binding transcription factor, which plays an important role in the regulation of oxidative stress, hemoglobin, and iron metabolism (37). BACH1 regulates EMT through modulation of intercellular adhesion genes, such as claudin3 and claudin4.…”

Section: Btb and Cnc Homologue 1 (Bach1)mentioning

confidence: 99%

Advances in the relationship between ferroptosis and epithelial–mesenchymal transition in cancer

Mu,

Zhou,

Shao

et al. 2023

Front. Oncol.

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Epithelial-mesenchymal transition (EMT) is a cellular reprogramming process that converts epithelial cells into mesenchymal-like cells with migratory and invasive capabilities. The initiation and regulation of EMT is closely linked to a range of transcription factors, cell adhesion molecules and signaling pathways, which play a key role in cancer metastasis and drug resistance. The regulation of ferroptosis is intricately linked to various cell death pathways, intracellular iron homeostasis, and the protein network governing iron supply and storage. The ability of ferroptosis to disrupt cancer cells and overcome drug resistance lies in its control of intracellular iron ion levels. EMT process can promote the accumulation of iron ions, providing conditions for ferroptosis. Conversely, ferroptosis may impact the regulatory network of EMT by modulating transcription factors, signaling pathways, and cell adhesion molecules. Thus, ferroptosis related genes and signaling pathways and oxidative homeostasis play important roles in the regulation of EMT. In this paper, we review the role of ferroptosis related genes and their signaling pathways in regulating cancer EMT to better understand the crosstalk mechanism between ferroptosis and EMT, aiming to provide better therapeutic strategies for eradicating cancer cells and overcoming drug resistance.

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Ferroptosis is programmed by the coordinated regulation of glutathione and iron metabolism by BACH1

Cited by 5 publications

References 58 publications

Cysteine restriction induces ferroptosis depending on the polyamine biosynthetic pathway in hepatic cancer cells

Cysteine restriction induces ferroptosis depending on the polyamine biosynthetic pathway in hepatic cancer cells

The Role of Labile Iron on Brain Proteostasis; Could it be an Early Event of Neurodegenerative Disease?

Advances in the relationship between ferroptosis and epithelial–mesenchymal transition in cancer

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