Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death

Dixon, Scott J.; Winter, Georg E.; Musavi, Leila; Lee, Eric D.; Snijder, Berend; Rebsamen, Manuele; Superti‐Furga, Giulio; Stockwell, Brent R.

doi:10.1021/acschembio.5b00245

Cited by 763 publications

(604 citation statements)

References 26 publications

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“…Acetyl-CoA carboxylase alpha (encoding ACC1), the ratelimiting step in fatty-acid synthesis, seems to be not required for ferroptosis in certain cells. 21 Knockdown of ACC1 by RNAi or inhibition of ACC1 by 5-tetradecyloxy-2-furonic acid did not affect RSL3-and erastin-induced ferroptosis. 21 PUFAs such as AA and linolenic acid are substrates of lipoxygenases (LOX).…”

Section: Signaling Pathwaymentioning

confidence: 86%

“…21 Knockdown of ACC1 by RNAi or inhibition of ACC1 by 5-tetradecyloxy-2-furonic acid did not affect RSL3-and erastin-induced ferroptosis. 21 PUFAs such as AA and linolenic acid are substrates of lipoxygenases (LOX). LOX oxidizes PUFAs to their hydroperoxyl intermediates, including HPETE, in the case of AA.…”

Section: Signaling Pathwaymentioning

confidence: 86%

“…Two lipid metabolism-associated genes (lysophosphatidylcholine acyltransferase 3 (LPCAT3) and acyl-CoA synthetase long-chain family member 4 (ACSL4)) have been identified to promote RSL3 − and DPI7 (also known as ML162) − , but not erastin-induced ferroptosis by using haploid genetic screening in KBM7 cells. 21 The depletion of arachidonic acid (AA) and other PUFAs, following GPX4 inactivation, is required for the execution of ferroptosis. 5,22 ACSL4 acylates AA and LPCAT3 catalyzes the acylated AA into membrane phospholipids.…”

Section: Signaling Pathwaymentioning

confidence: 99%

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Ferroptosis: process and function

et al. 2016

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Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.

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Section: Signaling Pathwaymentioning

confidence: 86%

Section: Signaling Pathwaymentioning

confidence: 86%

Section: Signaling Pathwaymentioning

confidence: 99%

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Ferroptosis: process and function

et al. 2016

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“…A previous study demonstrated that deletion of ACSL4 and LPCAT3 prevents RSL3 and ML162-induced ferroptosis in KBM7 cells (51). Thus, inhibition of phospholipid synthesis may suppress ferroptotic cell death.…”

Section: Ferroptosis Is Induced By Lipid Peroxidation Cell Lines Selmentioning

confidence: 92%

Metabolic networks in ferroptosis (Review)

et al. 2018

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Abstract.Ferroptosis is an iron-dependent and peroxidation-driven form of cell death associated with multiple metabolic disorders and disrupted homeostasis. A number of metabolic processes and homeostasis are affected by ferroptosis. The molecules that regulate ferroptosis are involved in metabolic pathways that regulate cysteine exploitation, glutathione state, nicotinamide adenine dinucleotide phosphate function, lipid peroxidation and iron homeostasis. The present review summarizes the metabolic networks involved in ferroptosis based on previous studies, and discusses the function of ferroptosis in pathological processes, including cancer. Finally, the clinical significance of ferroptosis is highlighted, to provide evidence for further studies.

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“…There are compelling data indicating that, depending on cell type and the activated oncogene that is the driver, p53 uses one or more of these pathways for tumor suppression. In addition, more recently, the process of ferroptosis has been implicated in tumor suppression by p53; ferroptosis is an iron-mediated nonapoptotic cell death pathway that requires high reactive oxygen species and likely involves a lipid peroxide intermediate (Dixon et al 2012(Dixon et al , 2015Dixon and Stockwell 2014;Yang et al 2014). The regulation of ferroptosis by p53 is mediated in part by p53-dependent negative regulation of the cystine transporter SLC7A11 .…”

mentioning

confidence: 99%

An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model

et al. 2016

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A nonsynonymous single-nucleotide polymorphism at codon 47 in TP53 exists in African-descent populations (P47S, rs1800371; referred to here as S47). Here we report that, in human cell lines and a mouse model, the S47 variant exhibits a modest decrease in apoptosis in response to most genotoxic stresses compared with wild-type p53 but exhibits a significant defect in cell death induced by cisplatin. We show that, compared with wild-type p53, S47 has nearly indistinguishable transcriptional function but shows impaired ability to transactivate a subset of p53 target genes, including two involved in metabolism: Gls2 (glutaminase 2) and Sco2. We also show that human and mouse cells expressing the S47 variant are markedly resistant to cell death by agents that induce ferroptosis (ironmediated nonapoptotic cell death). We show that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Our data suggest that the S47 variant may contribute to increased cancer risk in individuals of African descent, and our findings highlight the need to assess the contribution of this variant to cancer risk in these populations. These data also confirm the potential relevance of metabolism and ferroptosis to tumor suppression by p53.

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Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death

Cited by 763 publications

References 26 publications

Ferroptosis: process and function

Ferroptosis: process and function

Metabolic networks in ferroptosis (Review)

An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model

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