Open AccessLipoxygenase‐mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3
Author(s) -
Shintoku Ryosuke,
Takigawa Yuta,
Yamada Keiichi,
Kubota Chisato,
Yoshimoto Yuhei,
Takeuchi Toshiyuki,
Koshiishi Ichiro,
Torii Seiji
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13380
Subject(s) - lipid peroxidation , programmed cell death , reactive oxygen species , microbiology and biotechnology , cancer cell , gpx4 , gene silencing , cell , lipoxygenase , chemistry , oxidative stress , biochemistry , apoptosis , biology , cancer , enzyme , superoxide dismutase , gene , genetics , glutathione peroxidase
In cancer cells the small compounds erastin and RSL 3 promote a novel type of cell death called ferroptosis, which requires iron‐dependent accumulation of lipid reactive oxygen species. Here we assessed the contribution of lipid peroxidation activity of lipoxygenases ( LOX ) to ferroptosis in oncogenic Ras‐expressing cancer cells. Several 12/15‐ LOX inhibitors prevented cell death induced by erastin and RSL 3. Furthermore, si RNA ‐mediated silencing of ALOX 15 significantly decreased both erastin‐induced and RSL 3‐induced ferroptotic cell death, whereas exogenous overexpression of ALOX 15 enhanced the effect of these compounds. Immunofluorescence analyses revealed that the ALOX 15 protein consistently localizes to cell membrane during the course of ferroptosis. Importantly, treatments of cells with ALOX 15‐activating compounds accelerated cell death at low, but not high doses of erastin and RSL 3. These observations suggest that tumor ferroptosis is promoted by LOX ‐catalyzed lipid hydroperoxide generation in cellular membranes.