論文

2017年7月

Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis

FREE RADICAL BIOLOGY AND MEDICINE
  • Shinya Toyokuni
  • ,
  • Fumiya Ito
  • ,
  • Kyoko Yamashita
  • ,
  • Yasumasa Okazaki
  • ,
  • Shinya Akatsuka

108
開始ページ
610
終了ページ
626
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.freeradbiomed.2017.04.024
出版者・発行元
ELSEVIER SCIENCE INC

Epidemiological data indicate a constant worldwide increase in cancer mortality, although the age of onset is increasing. Recent accumulation of genomic data on human cancer via next-generation sequencing confirmed that cancer is a disease of genome alteration. In many cancers, the Nrf2 transcription system is activated via mutations either in Nrf2 or Keap1 ubiquitin ligase, leading to persistent activation of the genes with antioxidative functions. Furthermore, deep sequencing of passenger mutations is clarifying responsible cancer causative agent (s) in each case, including aging, APOBEC activation, smoking and UV. Therefore, it is most likely that oxidative stress is the principal initiating factor in carcinogenesis, with the involvement of two essential molecules for life, iron and oxygen. There is evidence based on epidemiological and animal studies that excess iron is a major risk for carcinogenesis, suggesting the importance of ferroptosis-resistance. Microscopic visualization of catalytic Fe (II) has recently become available. Although catalytic Fe(II) is largely present in lysosomes, proliferating cells harbor catalytic Fe(II) also in the cytosol and mitochondria. Oxidative stress catalyzed by Fe(II) is counteracted by thiol systems at different functional levels. Nitric oxide, carbon monoxide and hydrogen (per) sulfide modulate these reactions. Mitochondria generate not only energy but also heme/iron sulfur cluster cofactors and remain mostly dysfunctional in cancer cells, leading to Warburg effects. Cancer cells are under persistent oxidative stress with a delicate balance between catalytic iron and thiols, thereby escaping ferroptosis. Thus, high-dose L-ascorbate and non-thermal plasma as well as glucose/glutamine deprivation may provide additional benefits as cancer therapies over preexisting therapeutics.

リンク情報
DOI
https://doi.org/10.1016/j.freeradbiomed.2017.04.024
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/28433662
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000403463500055&DestApp=WOS_CPL
ID情報
  • DOI : 10.1016/j.freeradbiomed.2017.04.024
  • ISSN : 0891-5849
  • eISSN : 1873-4596
  • PubMed ID : 28433662
  • Web of Science ID : WOS:000403463500055

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