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      Acsl4 Dictates Ferroptosis Sensitivity by Shaping Cellular Lipid Composition

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          Abstract

          Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate this form of cell death are needed. We applied two independent approaches, a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines to uncover acyl-CoA synthetase long-chain family member 4 (Acsl4) as an essential component for ferroptosis execution. Specifically, Gpx4/Acsl4 double knockout cells presented an unprecedented resistance to ferroptosis. Mechanistically, Acsl4 enriches cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, Acsl4 is preferentially expressed in a panel of basal-like breast cancer cell lines and predicts their sensitivity to ferroptosis. We further demonstrate that pharmacological targeting of Acsl4 with the antidiabetic compound class, thiazolidinediones, ameliorates tissue demise in a murine model of ferroptosis, suggesting that Acsl4 inhibition is a viable therapeutic approach to prevent ferroptosis-related diseases.

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          Most cited references34

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          Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: Applications to mammalian blood and other tissues

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            Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells.

            We used synthetic lethal high-throughput screening to interrogate 23,550 compounds for their ability to kill engineered tumorigenic cells but not their isogenic normal cell counterparts. We identified known and novel compounds with genotype-selective activity, including doxorubicin, daunorubicin, mitoxantrone, camptothecin, sangivamycin, echinomycin, bouvardin, NSC146109, and a novel compound that we named erastin. These compounds have increased activity in the presence of hTERT, the SV40 large and small T oncoproteins, the human papillomavirus type 16 (HPV) E6 and E7 oncoproteins, and oncogenic HRAS. We found that overexpressing hTERT and either E7 or LT increased expression of topoisomerase 2alpha and that overexpressing RAS(V12) and ST both increased expression of topoisomerase 1 and sensitized cells to a nonapoptotic cell death process initiated by erastin.
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              Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death.

              Oxidative stress in conjunction with glutathione depletion has been linked with various acute and chronic degenerative disorders, yet the molecular mechanisms have remained unclear. In contrast to the belief that oxygen radicals are detrimental to cells and tissues by unspecific oxidation of essential biomolecules, we now demonstrate that oxidative stress is sensed and transduced by glutathione peroxidase 4 (GPx4) into a-yet-unrecognized cell-death pathway. Inducible GPx4 inactivation in mice and cells revealed 12/15-lipoxygenase-derived lipid peroxidation as specific downstream event, triggering apoptosis-inducing factor (AIF)-mediated cell death. Cell death could be entirely prevented either by alpha-tocopherol (alpha-Toc), 12/15-lipoxygenase inhibitors, or siRNA-mediated AIF silencing. Accordingly, 12/15-lipoxygenase-deficient cells were highly resistant to glutathione depletion. Neuron-specific GPx4 depletion caused neurodegeneration in vivo and ex vivo, highlighting the importance of this pathway in neuronal cells. Since oxidative stress is common in the etiology of many human disorders, the identified pathway reveals promising targets for future therapies.
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                Author and article information

                Journal
                101231976
                32624
                Nat Chem Biol
                Nat. Chem. Biol.
                Nature chemical biology
                1552-4450
                1552-4469
                7 September 2017
                14 November 2016
                January 2017
                23 September 2017
                : 13
                : 1
                : 91-98
                Affiliations
                [1 ]Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
                [2 ]University of Pittsburgh, Department of Environmental and Occupational Health, Pittsburgh, PA 15219, USA
                [3 ]Helmholtz Zentrum München, Institute of Stem Cell Biology, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
                [4 ]Helmholtz Zentrum München, Institute of Experimental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
                [5 ]Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
                [6 ]Helmholtz Zentrum München, Institute of Human Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
                [7 ]University of Heidelberg, Department of Gastroenterology, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany
                Author notes
                [*]

                these authors share co-senior authorship

                Article
                PMC5610546 PMC5610546 5610546 nihpa876501
                10.1038/nchembio.2239
                5610546
                27842070
                03e6c574-5aae-4cbd-9135-53be5308ffdd
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