Heme oxygenase-1 mediates BAY 11–7085 induced ferroptosis

Chang, Ling; Chiang, Shih Kai; Chen, Shuen-Ei; Yu, Yung Luen; Chou, Ruey Hwang; Chang, Wei Chao

doi:10.1016/j.canlet.2017.12.025

Cited by 401 publications

(283 citation statements)

References 59 publications

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“…BAY compounds are cysteine reactive and can form covalent adducts with a number of proteins in the cell (Pierce et al, 1997; Strickson et al, 2013; Yu et al, 2018). There is some evidence that these compounds may induce ferroptosis (Chang et al, 2018). Sensitivity to BAY-11–7821 was enhanced by pretreatment with the de novo GSH biosynthesis inhibitor BSO, suggesting that the lethality of this compound is opposed by GSH (Figure 4E).…”

Section: Resultsmentioning

confidence: 99%

A Genome-wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity

et al. 2019

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SUMMARYThe tripeptide glutathione suppresses the iron-dependent, non-apoptotic cell death process of ferroptosis. How glutathione abundance is regulated in the cell and how this regulation alters ferroptosis sensitivity is poorly understood. Using genome-wide human haploid genetic screening technology coupled to fluorescence-activated cell sorting (FACS), we directly identify genes that regulate intracellular glutathione abundance and characterize their role in ferroptosis regulation. Disruption of the ATP binding cassette (ABC)-family transporter multidrug resistance protein 1 (MRP1) prevents glutathione efflux from the cell and strongly inhibits ferroptosis. High levels of MRP1 expression decrease sensitivity to certain pro-apoptotic chemotherapeutic drugs, while collaterally sensitizing to all tested pro-ferroptotic agents. By contrast, disruption of KEAP1 and NAA38, leading to the stabilization of the transcription factor NRF2, increases glutathione levels but only weakly protects from ferroptosis. This is due in part to concomitant NRF2-mediated upregulation of MRP1. These results pinpoint glutathione efflux as an unanticipated regulator of ferroptosis sensitivity.

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Section: Resultsmentioning

confidence: 99%

A Genome-wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity

et al. 2019

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“…Ferroptosis is a novel cell death mechanism independent on caspase . In recent years, accumulating evidences identified ferroptosis as a defensive mechanism against cancer, neurotoxicity, and ischemia/reperfusion‐induced injury .…”

Section: Discussionmentioning

confidence: 99%

“…In a word, ART can ameliorate hepatic fibrosis and inhibit HSC activation in vivo and in vitro. Ferroptosis is a novel cell death mechanism independent on caspase (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). In recent years, accumulating evidences identified ferroptosis as a defensive mechanism against cancer, neurotoxicity, and ischemia/reperfusion-induced injury (10,43,44).…”

Section: Discussionmentioning

confidence: 99%

P53‐dependent induction of ferroptosis is required for artemether to alleviate carbon tetrachloride‐induced liver fibrosis and hepatic stellate cell activation

et al. 2018

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Ferroptosis is recently reported as a new mode of regulated cell death. Its essential characteristics are disturbed redox homeostasis, overloaded iron, and increased lipid peroxidation. However, the role of ferroptosis in liver fibrosis remains poorly understood. In this study, we attempted to investigate the effect of artemether (ART) on ferroptosis in hepatic fibrosis and to further clarify the possible mechanisms. Our data showed that ART treatment markedly attenuated liver injury and reduced fibrotic scar formation in the mouse model of liver fibrosis. Moreover, experiments in vitro also confirmed that ART treatment significantly decreased expression of hepatic stellate cell (HSC) activation markers. Interestingly, HSCs treated by ART presented morphological features of ferroptosis. Furthermore, ART remarkably triggered ferroptosis by promoting the accumulation of iron and lipid peroxides, whereas inhibition of ferroptosis by specific inhibitor ferrostatin‐1 (Fer‐1) completely abolished ART‐induced antifibrosis effect. More importantly, our discovery determined that tumor suppressor P53 was an upstream molecule in the facilitation of ART‐induced HSC ferroptosis. Conversely, knockdown of P53 by siRNA evidently blocked ART‐induced HSC ferroptosis in turn exacerbated liver fibrosis. Overall, our findings revealed that P53‐dependent induction of ferroptosis is necessary for ART to ameliorate CCl4‐induced hepatic fibrosis and inhibit HSC activation. © 2018 IUBMB Life, 71(1):45–56, 2019

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“…It showed a cytoprotective effect against oxidative response, whereas its function in ferroptosis is still not very clear [22]. Upregulation of HO-1 induced cellular ferrous accumulation and ferroptosis in breast cancer cell lines by BAY11-7085 [23]. In contrast, HO-1 mitigates ferroptosis in hepatocellular carcinoma cells and renal proximal tubule cells.…”

Section: Discussionmentioning

confidence: 99%

Nrf2 represses ER stress-related ferroptosis in renal carcinoma cells via HO-1

Shen

Tian

et al. 2020

Preprint

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Selective-induction of regulated cell death is considered as a useful strategy for developing effective therapies against renal cell carcinoma (RCC). In this study, the role of nuclear factor-E2-related factor 2 (Nrf2) and its downstream genes in erastin-induced ferroptosis of renal carcinoma cells was investigated. Erastin induced endoplasmic reticulum (ER) stress and ferroptosis in renal carcinoma cells (786-0 and Caki-1), which was confirmed by morphological changes, increased lipid oxidation and ferroptosis inhibition. Data obtained from TCGA dataset showed that Nrf2 and heme oxygenase-1 (HO-1) were not only significantly differentially expressed between RCC and normal samples, but also associated with better survival in RCC patients. Moreover, the process of ferroptosis induced by erastin in renal carcinoma cells was accompanied by increased expression of Nrf2 and HO-1. Inhibition of Nrf2 or HO-1 expression enhanced lipid ROS accumulation and ferroptosis. Furthermore, pharmacological activation of HO-1 reversed ferroptosis-sensitizing effect of Nrf2 silencing, thereby clarifying the key role of Nrf2/HO-1 pathway in erastin-induced ferroptosis in renal carcinoma cells. In summary, we identified the role of Nrf2/HO-1 signaling pathway in the protection of renal carcinoma cells from ER stress-related ferroptosis, which indicated that targeting of Nrf2/HO-1 pathway as a viable treatment strategy for RCC. Graphical abstract (supplementary figure):Nrf2 protects against ER stress-related ferroptosis via HO-1 in renal cancer cells.Cystine/glutamate antiporter (SLC7A11) abbreviated as xCT. Mitochondria abbreviated as Mito.

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Heme oxygenase-1 mediates BAY 11–7085 induced ferroptosis

Cited by 401 publications

References 59 publications

A Genome-wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity

A Genome-wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity

P53‐dependent induction of ferroptosis is required for artemether to alleviate carbon tetrachloride‐induced liver fibrosis and hepatic stellate cell activation

Nrf2 represses ER stress-related ferroptosis in renal carcinoma cells via HO-1

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