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群馬大学 生体調節研究所

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Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by anti-tumor FIN drugs.

Ryosuke Shintoku 1,2, Yuta Takigawa 3, Keiichi Yamada 4, Chisato Kubota 1, Yuhei Yoshimoto 2, Toshiyuki Takeuchi 1, Ichiro Koshiishi 3, Seiji Torii 1 (1: IMCR, Gunma Univ.; 2: Gunma Univ Grad Sch of Med; 3: Gunma Univ Grad Sch of Health Sci; 4: Grad Sch of Sci and Tech, Gunma Univ.)

About

In cancer cells the small compounds FINs (e.g. 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 (LOXs) 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- 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.

Paper information

Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3.
Ryosuke Shintoku, Yuta Takigawa, Keiichi Yamada, Chisato Kubota, Yuhei Yoshimoto, Toshiyuki Takeuchi, Ichiro Koshiishi, Seiji Torii
Cancer Sci 108, 2187-2194, 2017 doi: 10.1111/cas.13380

Online URL

http://www.ncbi.nlm.nih.gov/pubmed/28837253

Lab HP

http://secret-biol.imcr.gunma-u.ac.jp/

 

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