Lipoxygenase‐mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3. Issue 11 (15th September 2017)

• Record Type: Journal Article
• Authors: Shintoku, Ryosuke; Takigawa, Yuta; Yamada, Keiichi; Kubota, Chisato; Yoshimoto, Yuhei; Takeuchi, Toshiyuki; Koshiishi, Ichiro; Torii, Seiji
• Is Part Of: Cancer science. Volume 108:Issue 11(2017)
• Page Start: 2187
• Page End: 2194
• Publication Date: 2017-09-15
• Subjects: Cell death -- glutathione peroxidase -- iron -- Ras -- reactive oxygen species; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.13380
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract : 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. Abstract : 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.