A02：Breakdown of iron regulatory mechanisms in ferroptosis
Shinya TOYOKUNI
（Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine）
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Iron is an essential nutrient for all kinds of species on earth. However, iron provides double edged sword; its deficiency causes anemia in mammals but its excess leads to toxic effects. Indeed, excess iron in various pathology has been associated with carcinogenesis. Ferric nitrilotriacetate-induced renal cancers in wild-type rats present similar genetic alterations to their counterparts in humans. Ferroptosis is defined as a form of regulated necrosis, characterized by lipid peroxidation through high iron(oxidants)/sulfur(antioxidants) ratio. Considering that cancer cells generally reserve more catalytic Fe(II) than non-tumorous counterparts, many iron-induced carcinogenesis models, including asbestos-induced mesothelioma, suggest that cancer is a state of “iron addiction with ferroptosis-resistance.” The concept of ferroptosis is now expanding, and ferroptosis is observed not only in pathological conditions but also in certain physiological conditions. We try to understand precise iron regulatory mechanisms via cytosolic Fe(II) chaperone molecule, PCBP2, as well.
Major publications
Z. Li, L. Jiang, S.H. Chew, T. Hirayama, Y. Sekido, S. Toyokuni
“Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia”
Redox Biol. 2019, 26, 101297
doi: 10.1016/j.redox.2019.101297
I. Yanatori, D.R. Richardson, S. Toyokuni, F. Kishi
“How iron is handled in the course of heme catabolism: Integration of heme oxygenase with intracellular iron transport mechanisms mediated by poly (rC)-binding protein-2”
Arch. Biochem. Biophys. 2019, 672, 108071
doi:10.1016/j.abb.2019.108071
S. Toyokuni
“Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention”
Free Radic. Biol. Med. 2019,133, 206-215
doi: 10.1016/j.freeradbiomed.2018.10.401
Y. Ohara, S.H. Chew, T. Shibata, Y. Okazaki, K. Yamashita, S. Toyokuni
“Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats”
Cancer Sci. 2018, 109, 330-339
doi:10.1111/cas.13460
B.R. Stockwell, J.P. Friedmann Angeli, H. Bayir, A.I. Bush, M. Conrad, S.J. Dixon, S. Fulda, S. Gascón, S.K. Hatzios, V.E. Kagan, K. Noel, X. Jiang, A. Linkermann, M.E. Murphy, M. Overholtzer, A. Oyagi, G.C. Pagnussat, J. Park, Q. Ran, C.S. Rosenfeld, K. Salnikow, D. Tang, F.M. Torti, S.V. Torti, S. Toyokuni, K.A. Woerpel, D.D. Zhang
“Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease”
Cell 2017, 171, 273-285
doi:10.1016/j.cell.2017.09.021
S. Toyokuni, F. Ito, K. Yamashita, Y. Okazaki, S. Akatsuka
“Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis”
Free Radic. Biol. Med. 2017, 108, 610-626
doi: 10.1016/j.freeradbiomed.2017.04.024
S. Toyokuni
“The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosis-resistance to non-thermal plasma therapy”
Pathol. Int. 2016, 66, 245-259
doi:10.1111/pin.12396
S. Akatsuka, Y. Yamashita, H. Ohara, Y.T. Liu, M. Izumiya, K. Abe, M. Ochiai, L. Jiang, H. Nagai, Y. Okazaki, H. Murakami, Y. Sekido, E. Arai, Y. Kanai, O. Hino, T. Takahashi, H. Nakagama, S. Toyokuni
“Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer”
PLoS One 2012, 7, e43403
doi: 10.1371/journal.pone.0043403