title: Lipid Peroxidation-Dependent Cell Death Regulated by GPx4 and Ferroptosis.
abstract: Glutathione peroxidase 4 (Phospholipid hydroperoxide glutathione peroxidase, PHGPx) can directly reduce phospholipid hydroperoxide. Depletion of GPx4 induces lipid peroxidation-dependent cell death in embryo, testis, brain, liver, heart, and photoreceptor cells of mice. Administration of vitamin E in tissue specific GPx4 KO mice restored tissue damage in testis, liver, and heart. These results indicate that suppression of phospholipid peroxidation is essential for cell survival in normal tissues in mice. Ferroptosis is an iron-dependent non-apoptotic cell death that can elicited by pharmacological inhibiting the cystine/glutamate antiporter, system Xc-(type I) or directly binding and loss of activity of GPx4 (Type II) in cancer cells with high level RAS-RAF-MEK pathway activity or p53 expression, but not in normal cells. Ferroptosis by Erastin (Type I) and RSL3 (RAS-selective lethal 3, Type II) treatment was suppressed by an iron chelator, vitamin E and Ferrostatin-1, antioxidant compound. GPx4 can regulate ferroptosis by suppression of phospholipid peroxidation in erastin and RSL3-induced ferroptosis. Recent works have identified several regulatory factors of erastin and RSL3-induced ferroptosis. In our established GPx4-deficient MEF cells, depletion of GPx4 induce iron and 15LOX-independent lipid peroxidation at 26 h and caspase-independent cell death at 72 h, whereas erastin and RSL3 treatment resulted in iron-dependent ferroptosis by 12 h. These results indicated the possibility that the mechanism of GPx4-depleted cell death might be different from that of ferroptosis induced by erastin and RSL3.
authors.affiliation: Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan. imaih@pharm.kitasato-u.ac.jp.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Imai
authors.affiliation: Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsuoka
authors.affiliation: Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kumagai
authors.affiliation: Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Koumura
mesh_terms: D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D003514:Cyclohexylamines / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000502:physiology*; D010655:Phenylenediamines / Q000378:metabolism*; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D010879:Piperazines / Q000494:pharmacology
chemical_list: D002243:Carbolines; D003514:Cyclohexylamines; D010655:Phenylenediamines; D010879:Piperazines; C587550:RSL3 compound; C477224:erastin; C573944:ferrostatin-1; D007501:Iron; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D020169:Caspases