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

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          Abstract

          Little is known about the regulation of nonapoptotic cell death. Using massive insertional mutagenesis of haploid KBM7 cells we identified nine genes involved in small-molecule-induced nonapoptotic cell death, including mediators of fatty acid metabolism ( ACSL4) and lipid remodeling ( LPCAT3) in ferroptosis. One novel compound, CIL56, triggered cell death dependent upon the rate-limiting de novo lipid synthetic enzyme ACC1. These results provide insight into the genetic regulation of cell death and highlight the central role of lipid metabolism in nonapoptotic cell death.

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          RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels.

          Nicholas Yagoda, Moritz von Rechenberg, Elma Zaganjor … (2007)
          Therapeutics that discriminate between the genetic makeup of normal cells and tumour cells are valuable for treating and understanding cancer. Small molecules with oncogene-selective lethality may reveal novel functions of oncoproteins and enable the creation of more selective drugs. Here we describe the mechanism of action of the selective anti-tumour agent erastin, involving the RAS-RAF-MEK signalling pathway functioning in cell proliferation, differentiation and survival. Erastin exhibits greater lethality in human tumour cells harbouring mutations in the oncogenes HRAS, KRAS or BRAF. Using affinity purification and mass spectrometry, we discovered that erastin acts through mitochondrial voltage-dependent anion channels (VDACs)--a novel target for anti-cancer drugs. We show that erastin treatment of cells harbouring oncogenic RAS causes the appearance of oxidative species and subsequent death through an oxidative, non-apoptotic mechanism. RNA-interference-mediated knockdown of VDAC2 or VDAC3 caused resistance to erastin, implicating these two VDAC isoforms in the mechanism of action of erastin. Moreover, using purified mitochondria expressing a single VDAC isoform, we found that erastin alters the permeability of the outer mitochondrial membrane. Finally, using a radiolabelled analogue and a filter-binding assay, we show that erastin binds directly to VDAC2. These results demonstrate that ligands to VDAC proteins can induce non-apoptotic cell death selectively in some tumour cells harbouring activating mutations in the RAS-RAF-MEK pathway.
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            Synchronized renal tubular cell death involves ferroptosis.

            Andreas Linkermann, Rachid Skouta, Nina Himmerkus … (2014)
            Receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is thought to be the pathophysiologically predominant pathway that leads to regulated necrosis of parenchymal cells in ischemia-reperfusion injury (IRI), and loss of either Fas-associated protein with death domain (FADD) or caspase-8 is known to sensitize tissues to undergo spontaneous necroptosis. Here, we demonstrate that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury. In contrast, iron-dependent ferroptosis directly causes synchronized necrosis of renal tubules, as demonstrated by intravital microscopy in models of IRI and oxalate crystal-induced acute kidney injury. To suppress ferroptosis in vivo, we generated a novel third-generation ferrostatin (termed 16-86), which we demonstrate to be more stable, to metabolism and plasma, and more potent, compared with the first-in-class compound ferrostatin-1 (Fer-1). Even in conditions with extraordinarily severe IRI, 16-86 exerts strong protection to an extent which has not previously allowed survival in any murine setting. In addition, 16-86 further potentiates the strong protective effect on IRI mediated by combination therapy with necrostatins and compounds that inhibit mitochondrial permeability transition. Renal tubules thus represent a tissue that is not sensitized to necroptosis by loss of FADD or caspase-8. Finally, ferroptosis mediates postischemic and toxic renal necrosis, which may be therapeutically targeted by ferrostatins and by combination therapy.
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              Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models

              Rachid Skouta, Scott J. Dixon, Jianlin Wang … (2014)
              Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. We found that Fer-1 inhibited cell death in cellular models of Huntington’s disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1 inhibited lipid peroxidation, but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. We developed a mechanistic model to explain the activity of Fer-1, which guided the development of ferrostatins with improved properties. These studies suggest numerous therapeutic uses for ferrostatins, and that lipid peroxidation mediates diverse disease phenotypes.
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                Author and article information

                Journal
                Journal ID (nlm-ta): ACS Chem Biol
                Journal ID (iso-abbrev): ACS Chem. Biol
                Journal ID (publisher-id): cb
                Journal ID (coden): acbcct
                Title: ACS Chemical Biology
                Publisher: American Chemical Society
                ISSN (Print): 1554-8929
                ISSN (Electronic): 1554-8937
                Publication date PMC-release: 12 May 2016
                Publication date (Electronic): 12 May 2015
                Publication date (Print): 17 July 2015
                Volume: 10
                Issue: 7
                Pages: 1604-1609
                Affiliations
                [1] †Department of Biological Sciences, ‡Department of Chemistry, and §Howard Hughes Medical Institute, Columbia University , 550 West 120th Street, Northwest Corner Building, MC 4846, New York, New York 10027, United States
                [∥ ]CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences , Lazarettgasse 14, 1090 Vienna, Austria
                [⊥ ]Department of Biology, Stanford University , 337 Campus Drive, Stanford, California 94305, United States
                Author notes
                Article
                DOI: 10.1021/acschembio.5b00245
                PMC ID: 4509420
                PubMed ID: 25965523
                SO-VID: b7bbb6cf-2e65-4292-b0ab-547bd97d9902
                Copyright © Copyright © 2015 American Chemical Society
                License:

                This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

                History
                Date received : 06 April 2015
                Date accepted : 12 May 2015
                Categories
                Subject: Letters
                Custom metadata
                document-id-old-9 cb5b00245
                document-id-new-14 cb-2015-002457
                ccc-price

                ScienceOpen disciplines: Biochemistry
                Data availability:
                ScienceOpen disciplines: Biochemistry

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