Slowly progressive cell death induced by GPx4-deficiency occurs via MEK1/ERK2 activation as a downstream signal after iron-independent lipid peroxidation

DOI Web Site 参考文献29件
  • Tsuruta Kahori
    Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University Laboratory of Microbiology, School of Pharmaceutical Sciences, Kitasato University
  • Matsuoka Masaki
    Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University
  • Harada Shinsaku
    Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University
  • Enomoto Ayaka
    Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University
  • Kumagai Takeshi
    Laboratory of Clinical Pharmacy Research, School of Pharmaceutical Sciences, Kitasato University
  • Yasuda Shu
    Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University
  • Koumura Tomoko
    Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University
  • Yamada Ken-ichi
    Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Kyushu University
  • Imai Hirotaka
    Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University Medical Research Laboratories, School of Pharmaceutical Sciences, Kitasato University

説明

<p>Glutathione peroxidase 4 (GPx4) is an antioxidant enzyme that reduces phospholipid hydroperoxide. Studies have reported that the loss of GPx4 activity through anticancer drugs leads to ferroptosis, an iron-dependent lipid peroxidation-induced cell death. In this study, we established Tamoxifen-inducible GPx4-deficient Mouse embryonic fibroblast (MEF) cells (ETK1 cells) and found that Tamoxifen-inducible gene disruption of GPx4 induces slow cell death at ~72 ‍h. In contrast, RSL3- or erastin-induced ferroptosis occurred quickly within 24 ‍h. Therefore, we investigated the differences in these mechanisms between GPx4 gene disruption-induced cell death and RSL3- or erastin-induced ferroptosis. We found that GPx4-deficiency induced lipid peroxidation at 24 ‍h in Tamoxifen-treated ETK1 cells, which was not suppressed by iron chelators, although lipid peroxidation in RSL3- or erastin-treated cells induced ferroptosis that was inhibited by iron chelators. We revealed that GPx4-deficient cell death was MEK1-dependent but RSL3- or erastin-induced ferroptosis was not, although MEK1/2 inhibitors suppressed both GPx4-deficient cell death and RSL3- or erastin-induced ferroptosis. In GPx4-deficient cell death, the phosphorylation of MEK1/2 and ERK2 was observed 39 ‍h after lipid peroxidation, but ERK1 was not phosphorylated. Selective inhibitors of ERK2 inhibited GPx4-deficient cell death but not in RSL3- or erastin-induced cell death. These findings suggest that iron-independent lipid peroxidation due to GPx4 disruption induced cell death via the activation of MEK1/ERK2 as a downstream signal of lipid peroxidation in Tamoxifen-treated ETK1 cells. This indicates that GPx4 gene disruption induces slow cell death and involves a different pathway from RSL3- and erastin-induced ferroptosis in ETK1 cells.</p>

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