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Regulation of Ferroptotic Cancer Cell Death by GPX4
Open accessAbstract
Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death.
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In the citing paper
“the reduced glutathione (GSH)-dependent enzyme glutathione peroxidase 4 (GPX4)—which is directly targeted by RSL3—has emerged as the main endogenous inhibitor of ferroptosis by virtue of its ability to limit lipid peroxidation by catalyzing the GSH-dependent reduction of lipid hydroperoxides to lipid alcohols [547–550].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [548]
In the citing paper
“erastin triggers ferroptosis by (indirectly) affecting the catalytic cycle of GPX4 via a mechanism that involves the inhibition of the cystine/glutamate antiporter system xc− and consequent decrease in intracellular cysteine (which derives from cystine reduction in the cytoplasm) and GSH (which is synthesized from cysteine) [539, 548, 549, 551].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [548]
In the citing paper
“the ferroptosis-inhibiting effect of iron depletion by either chelators [539, 543, 548] or phosphorylase kinase catalytic subunit gamma 2 (PHKG2) knockdown [566]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [548]
In the citing paper
“Among these genes, we identified known regulators of apoptosis, such as TP53, IKBIP, and factors specifically of neuronal survival, such as XIAP17–20, GDPGP121 and MAP3K123,22–24, as well as genes not previously implicated in neuronal survival, such as IGF2BP1 and IGF2BP3.”
From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [19]
In the citing paper
“Inhibitors of this transporter have been found to deplete intracellular glutathione in cancer cells, resulting in iron-dependent accumulation of ROS and a form of cell death termed ferroptosis (Dixon et al., 2012; Dixon et al., 2014; Yang et al., 2014).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Yang et al., 2014
In the citing paper
“Moreover, glutathione is not depleted during RSL3-induced cell death [24], supporting the presence of an alternative ferroptosis-initiating mechanism for RSL3.”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [24]
In the citing paper
“Analysis of mass spectrometry-based proteomic data from an affinity pulldown experiment ranked GPX4 (glutathione peroxidase 4, PHGPx) as the top protein target for (1S,3R)-RSL3 [24]; western blotting further confirmed binding between (1S,3R)-RSL3 and GPX4.”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [24]
In the citing paper
“Glutathione depletion causes loss of cellular antioxidant capacity, as well as inhibition of glutathione-dependent enzymes, such as glutathione peroxidases [24, 25].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [24]
In the citing paper
“Moreover, knockdown of GPX4 expression generates lipid ROS and induces ferroptosis, supporting the hypothesis that (1S, 3R)-RSL3 induces ferroptosis through inhibition of GPX4 [24].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [24]
In the citing paper
“This glutathione depletion is sufficient for erastin-dependent cell death, as glutathione depletion by another reagent, buthionine sulfoxamine (BSO), also initiated ferroptosis [24].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [24]
In the citing paper
“Cell lysates prepared from (1S, 3R)-RSL3-treated cells could not reduce phosphatidylcholine hydroperoxides into the corresponding alcohols, demonstrating that RSL3 inhibits GPX4 enzyme activity [24].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [24]
In the citing paper
“The screening assay in which erastin and RSL3 were identified later revealed ten additional compounds that induce ferroptosis [24, 26]. All but one compound (DPI2) inhibited GPX4 directly, similar to RSL3. In contrast, DPI2 depleted GSH, like erastin [24].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [24]
In the citing paper
“Overexpression of GPX4 suppressed cell death induced by these compounds [24], but not other lethal agents, indicating that GPX4 is a specific and robust central regulator of ferroptotic cell death, akin to BCL-2 in apoptosis.”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [24]
In the citing paper
“Indeed, a metabolite profiling assay revealed that glutathione was the most decreased cellular metabolite during erastin-induced ferroptosis [24].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [24]
In the citing paper
“Although erastin displayed selective lethality in engineered cells overexpressing HRASG12V , there was no consistent difference in erastin sensitivity between wild-type and mutated RAS cells.”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [24]
In the citing paper
“Tubular cells in the kidney are also particularly susceptible to ferroptosis induction by Gpx4 deletion in vivo [15], which is intriguing in light of the enhanced sensitivity of renal cell carcinoma cell lines in culture to erastin [24].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [24]
In the citing paper
“Moreover, RCC was found to be particularly susceptible to erastin-induced ferroptosis compared to other tissues in the NCI-60 panel, a panel of cancer cell lines derived from eight different tissues [24].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [24]
In the citing paper
“In addition, the depletion of GPX4 can promote the accumulation of lipid peroxide and lipid free radicals, causing ferroptosis (Yang et al., 2014).”
From MiR-378a-3p/ SLC7A11 regulate ferroptosis in nerve injury induced by lead exposure (2022) · cites this paper as Yang et al., 2014
In the citing paper
“Lipid peroxidation is an important characteristic of ferroptosis and is strongly regulated by GPX4 and GSH (Chen et al., 2015;Yang et al., 2014).”
From MiR-378a-3p/ SLC7A11 regulate ferroptosis in nerve injury induced by lead exposure (2022) · cites this paper as Yang et al., 2014
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Metadata
- Authors
- Yang, W. S., SriRamaratnam, R., Welsch, M. E., Shimada, K., Skouta, R., Viswanathan, V. S., Cheah, J. H., Clemons, P. A., Shamji, A. F., Clish, C. B., Brown, L. M., Girotti, A. W., Cornish, V. W., Schreiber, S. L., & Stockwell, B. R.
- Affiliations
- Columbia University (US)
- Broad Institute (US)
- Medical College of Wisconsin (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Stockwell, Brent R.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 156
- Issue
- 1-2
- Pages
- 317-331
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4076414
- OpenAlex
- W2002490399
- Cited by
- 7,713
- References
- 48
- Citations by year
- 2026: 1070 · 2025: 1226 · 2024: 1343 · 2023: 1164 · 2022: 1041 · 2021: 759 · 2020: 421 · 2019: 256 · 2018: 151 · 2017: 115 · 2016: 86 · 2015: 53 · 2014: 25
- FWCI
- 74.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (CHE 0840451)
- New York State Stem Cell Science (C026715)
- Empire State Development's Division of Science, Technology and Innovation
- Arnold and Mabel Beckman Foundation
- National Institutes of Health (R01CA161061, 5R01CA097061, 5R01GM085081, 1S10RR025431-01A1)
- Broad Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- ferroptosis, GPX4, glutathione peroxidase, glutathione depletion, ferroptosis inducers, non-apoptotic cell death, cancer cell death, chemoproteomics, targeted metabolomics, diffuse large B-cell lymphoma, renal cell carcinoma, tumor growth inhibition
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Animals, Carbolines, Carcinoma, Renal Cell, Glutathione, Glutathione Peroxidase, Humans, Neoplasm Transplantation, Neoplasms, Piperazines, Lymphoma, B-Cell, Cell Death, Cell Line, Tumor, Mice, Gene Knockdown Techniques, Heterografts
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