Lipoxygenase‐mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3

• Published in: Cancer science Vol. 108; no. 11; pp. 2187 - 2194
• Main Authors: Shintoku, Ryosuke, Takigawa, Yuta, Yamada, Keiichi, Kubota, Chisato, Yoshimoto, Yuhei, Takeuchi, Toshiyuki, Koshiishi, Ichiro, Torii, Seiji
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.11.2017; John Wiley and Sons Inc
• Subjects: Apoptosis; Arachidonate 15-Lipoxygenase - genetics; Cancer; Carbolines - administration & dosage; Cell death; Cell Death - drug effects; Cell Line, Tumor; Cell membranes; Fatty acids; Ferroptosis; Fibrosarcoma - drug therapy; Fibrosarcoma - genetics; Fibrosarcoma - pathology; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; glutathione peroxidase; Humans; Immunofluorescence; Immunoglobulins; iron; Lipid peroxidation; Lipid Peroxidation - drug effects; Lipids; Lipoxygenase; Membranes; Original; Oxidation; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Piperazines - administration & dosage; Ras; Reactive oxygen species; RNA, Small Interfering; siRNA; United States > US; Japan; iron; Cell death; Ras; reactive oxygen species; glutathione peroxidase
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.13380

In cancer cells the small compounds erastin and RSL3 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 RSL3. Furthermore, siRNA‐mediated silencing of ALOX15 significantly decreased both erastin‐induced and RSL3‐induced ferroptotic cell death, whereas exogenous overexpression of ALOX15 enhanced the effect of these compounds. Immunofluorescence analyses revealed that the ALOX15 protein consistently localizes to cell membrane during the course of ferroptosis. Importantly, treatments of cells with ALOX15‐activating compounds accelerated cell death at low, but not high doses of erastin and RSL3. These observations suggest that tumor ferroptosis is promoted by LOX‐catalyzed lipid hydroperoxide generation in cellular membranes. The lipid‐peroxidizing enzyme (ALOX15) constitutively localizes on the cell membrane in human fibrosarcoma HT1080 cells, and cells with enhanced ALOX15 activity are more sensitive to ferroptosis‐inducing compounds.