Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers

Soula, Mariluz; Weber, Ross A.; Zilka, Omkar; Alwaseem, Hanan; La, Konnor; Yen, Frederick S.; Molina, Henrik; García‐Bermúdez, Javier; Pratt, Derek A.; Birsoy, Kıvanç

doi:10.1038/s41589-020-0613-y

Cited by 443 publications

(353 citation statements)

References 58 publications

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“…This phenomenon may also provide an explanation for why previous studies of APR-246-mediated cell death that relied on long term exposures (> 48 hr) with APR-246 and the use of cellular metabolism assays as surrogates for cellular viability failed to demonstrate rescue with ferroptosis inhibitors 6 . Furthermore, this is in keeping with recent findings that distinguish erastin, which block cystine import into cells, as maintaining cell proliferation activity in the presence of ferroptosis inhibitors 20 . Extending this, given that the proposed mechanism of action of APR-246 is to induce apoptotic cell death, we also genetically engineered the Mc38 mouse colon adenocarcinoma model to be completely deficient in the intrinsic apoptotic machinery (Bax/Bak/Bid/Casp3/Casp7 KO).…”

supporting

confidence: 90%

Genome-wide CRISPR screens reveal APR-246 (Eprenetapopt) triggers ferroptosis and inhibits iron-sulfur cluster biogenesis

Fujihara

Jackson

et al. 2020

Preprint

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The mechanisms by which cells respond and adapt to oxidative stress are largely unknown but are key to developing a rationale for cancer therapies that target antioxidant pathways. APR-246 is a mutant-p53 targeted therapeutic currently under clinical investigation in myeloid dysplastic syndrome (MDS) and acute myeloid leukemia1. Whilst the mechanism of action of APR-246 is thought to be reactivation of wild-type p53 activity through covalent modification of cysteine residues in the core domain of mutant-p53 protein2,3, here we report that the anti-neoplastic capacity of APR-246 lies predominantly in the conjugation of free cysteine. Genome-wide CRISPR perturbation screening, metabolite profiling and proteomics in response to APR-246 treatment in mutant-p53 cancer cells highlighted the role of GSH and mitochondrial metabolism in determining APR-246 efficacy. APR-246 sensitivity was increased through loss of key enzymes in mitochondrial one-carbon metabolism, SHMT2 and MTHFD1L, due to diminished glycine supply for de novo GSH synthesis. Critically, we show that APR-246 induces iron-dependent, apoptotic machinery-independent cell death, ferroptosis. Whole-cell proteomics analyses indicated an upregulation of proteins involved in iron-sulfur cluster biogenesis (eg. FDX1). GSH, acetyl-CoA and NADH levels were also depleted in APR-246 treated cells. Importantly, we found that APR-246 inhibits iron-sulfur cluster biogenesis in the mitochondria of cancer cells through cysteine conjugation. This work not only details novel determinants of APR-246 activity in cancer cells, but also provides a clinical roadmap for targeting antioxidant pathways in tumours - beyond targeting mutant-p53 tumours.

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supporting

confidence: 90%

Genome-wide CRISPR screens reveal APR-246 (Eprenetapopt) triggers ferroptosis and inhibits iron-sulfur cluster biogenesis

Fujihara

Jackson

et al. 2020

Preprint

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“…78 BH4 is a potent radicaltrapping antioxidant that protects cells from ferroptosis upon GPX4 inhibition by reducing lipid peroxidation and is regenerated by dihydrofolate reductase (DHFR). 142 Besides, nuclear factor erythroid 2-related factor 2 (Nrf2) may play a role in modulating the cellular ferroptosis response. Nrf2 is responsible for regulating several antioxidant genes.…”

Section: Antioxidant Mechanismsmentioning

confidence: 99%

Ferroptosis: mechanisms and links with diseases

Yan

Zou

Tuo

et al. 2021

Sig Transduct Target Ther

684

477

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Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death is defined by the accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin, liproxstatin). This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association with several pathways, including iron, lipid, and cysteine metabolism. We have further discussed the contribution of ferroptosis to the pathogenesis of several diseases such as cancer, ischemia/reperfusion, and various neurodegenerative diseases (e.g., Alzheimer’s disease and Parkinson’s disease), and evaluated the therapeutic applications of ferroptosis inhibitors in clinics.

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“…In support of the role of lipid peroxidation in ferroptosis, the classic ferroptosis inducers, such as erastin (Dixon et al, 2012) and RSL3 (Yang et al, 2014), are indeed inhibitors of the antioxidant system. The three antioxidant defense systems [referred to as glutathione (GSH; Dixon et al, 2012), coenzyme Q10 (CoQ10; Bersuker et al, 2019;Doll et al, 2019), or tetrahydrobiopterin (BH4) system (Kraft et al, 2020;Soula et al, 2020)] can work together or separately to limit ferroptotic death mediated by oxidative damage. The GSH system is the main pathway limiting ferroptosis.…”

Section: Loss Of Antioxidant Defensementioning

confidence: 99%

“…In addition to blocking the system xc − activity on the cell membrane, erastin is also a potential activator of mitochondrial voltage dependent anion channel 2/3 (VDAC2/3) (Yagoda et al, 2007), highlighting the participation of mitochondria dysfunction in erastin-induced ferroptosis. GPX4independent anti-ferroptosis pathway relies on the production of CoQ10 (Bersuker et al, 2019;Doll et al, 2019) or BH4 (Kraft et al, 2020;Soula et al, 2020), which is further regulated by apoptosis inducing factor mitochondria associated 2 (AIFM2/FSP1) or GTP cyclohydrolase 1 (GCH1), respectively. Interestingly, AIFM2 was previously thought to be a proapoptotic protein in mitochondria (Wu et al, 2002).…”

Section: Loss Of Antioxidant Defensementioning

confidence: 99%

Characteristics and Biomarkers of Ferroptosis

Chen

Comish

Tang

et al. 2021

Front. Cell Dev. Biol.

249

175

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The induction and consequences of regulated cell death (RCD) are accompanied by changes in gene and protein expression, biochemical pathways, as well as cell morphology and size. Such RCDs have a significant impact on development, tissue homeostasis, and the occurrence and progression of disease. Among different forms of RCD, ferroptosis appears to be the main cause of tissue damage driven by iron overload and lipid peroxidation. In fact, the dysfunctional ferroptotic response is implicated in a variety of pathological conditions and diseases, such as neurodegenerative diseases, tissue ischemia-reperfusion injury, tumorigenesis, infections, and immune diseases. Ferroptotic response can be fine-tuned through various oxidative stress and antioxidant defense pathways, coupling with metabolism, gene transcription, and protein degradation machinery. Accordingly, a series of ferroptosis inducers or inhibitors targeting redox- or iron metabolism-related proteins or signal transduction have been developed. Although this kind of RCD has recently attracted great interest in basic and clinical research, detecting and monitoring a ferroptotic response still faces challenges. In this mini-review, we not only summarize the latest knowledge about the characteristics of ferroptosis in vitro and in vivo, but also discuss the specificity and limitations of current biomarkers of ferroptosis.

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Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers

Cited by 443 publications

References 58 publications

Genome-wide CRISPR screens reveal APR-246 (Eprenetapopt) triggers ferroptosis and inhibits iron-sulfur cluster biogenesis

Genome-wide CRISPR screens reveal APR-246 (Eprenetapopt) triggers ferroptosis and inhibits iron-sulfur cluster biogenesis

Ferroptosis: mechanisms and links with diseases

Characteristics and Biomarkers of Ferroptosis

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