Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death

Kwon, Mi Young; Park, Eun-Hee; Lee, Seon-Jin; Chung, Sung Min

doi:10.18632/oncotarget.5162

Cited by 487 publications

(378 citation statements)

References 30 publications

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“…A candidate family of enzymes with this property is the family of lipoxygenases that catalyze the dioxygenation of polyunsaturated fatty acids in lipids [86]. In addition, the iron-containing heme oxygenase-1 (HO-1) was reported to be induced upon erastin treatment and to accelerate erastin-induced ferroptosis[87]; thus, HO-1 may be a source of iron driving the lipid peroxidation that occurs during ferroptosis, at least in response to erastin.…”

Section: Resultsmentioning

confidence: 99%

Ferroptosis: Death by Lipid Peroxidation

Yang

Stockwell

2016

Trends in Cell Biology

2,199

1,468

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Ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and subsequent accumulation of lipid-based reactive oxygen species, particularly lipid hydroperoxides. This form of iron-dependent cell death is genetically, biochemically, and morphologically distinct from other cell death modalities, including apoptosis, unregulated necrosis, and necroptosis. Ferroptosis is regulated by specific pathways and is involved in diverse biological contexts. Here, we summarize the discovery of ferroptosis, the mechanism of ferroptosis regulation, and its increasingly appreciated relevance to both normal and pathological physiology.

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Section: Resultsmentioning

confidence: 99%

Ferroptosis: Death by Lipid Peroxidation

Yang

Stockwell

2016

Trends in Cell Biology

2,199

1,468

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“…HMOX1 is necessary for ferroptosis and is a major source of iron in the body. [29] Inhibition of cysteine-glutamate exchange through System x c- , of which SLC7A11 is a component, induces iron-dependent cell death. [30] To determine whether 35G8 induces ferroptosis in U87MG cells, we treated the cells in the presence or absence of deferoxamine (DFO), an iron chelator (Figure S2B).…”

Section: Resultsmentioning

confidence: 99%

“…[29, 30] SLC7A11 is a negative regulator of ferroptosis and upregulation of SLC7A11 occurs as a response to system x c- inhibition. [13] Efforts to treat glioma patients by inhibiting system x c- have failed; [45] however, combining SLC7A11 inhibition with a PDI inhibitor may be a promising new strategy.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Mechanistic Elucidation of a Class of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma

et al. 2018

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Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblastoma cell lines. We performed a medium-throughput 20 000-compound screen of a diverse subset of 1 000 000 compounds to identify cytotoxic small molecules. Cytotoxic compounds were screened for PDI inhibition, and, from the screen, 35G8 emerged as the most cytotoxic inhibitor of PDI. Bromouridine labeling and sequencing (Bru-seq) of nascent RNA revealed that 35G8 induces nuclear factor-like 2 (Nrf2) antioxidant response, endoplasmic reticulum (ER) stress response, and autophagy. Specifically, 35G8 upregulated heme oxygenase 1 and solute carrier family 7 member 11 (SLC7A11) transcription and protein expression and repressed PDI target genes such as thioredoxin-interacting protein 1 (TXNIP) and early growth response 1 (EGR1). Interestingly, 35G8-induced cell death did not proceed via apoptosis or necrosis, but by a mixture of autophagy and ferroptosis. Cumulatively, our data demonstrate a mechanism for a novel PDI inhibitor as a chemical probe to validate PDI as a target for brain cancer.

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“…17 In contrast, induction of HO-1 expression by erastin may promote cell death in HT1080 and fibroblasts, suggesting that HO-1 has a dual role in ferroptosis. 37 Measuring methods…”

Section: Molecular Biologymentioning

confidence: 99%

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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Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death

Cited by 487 publications

References 30 publications

Ferroptosis: Death by Lipid Peroxidation

Ferroptosis: Death by Lipid Peroxidation

Discovery and Mechanistic Elucidation of a Class of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma

Ferroptosis: process and function

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