GPX4
脱氮酶
程序性细胞死亡
细胞凋亡
化学
细胞生物学
癌细胞
脂质过氧化
磷脂过氧化氢谷胱甘肽过氧化物酶
癌症研究
谷胱甘肽
生物化学
泛素
酶
生物
癌症
谷胱甘肽过氧化物酶
基因
遗传学
作者
Li Yang,Xin Chen,Qianqian Yang,Jinghong Chen,Qianru Huang,Leyi Yao,Yan Ding,Jiawen Wu,Peiquan Zhang,Daolin Tang,Nanshan Zhong,Jinbao Liu
标识
DOI:10.3389/fonc.2020.00949
摘要
Proteasomal deubiquitinase (DUB) inhibition has been found to be effective in experimental cancer therapy by inducing proteasome inhibition and apoptosis. Ferroptosis is a form of regulated cell death characterized by an iron-dependent lipid peroxidation. Antioxidant enzyme glutathione peroxidase 4 (GPX4) plays a key role in blocking ferroptosis through directly reducing phospholipid hydroperoxides production. Since cytoplasmic DUB inhibition can promote protein degradation in the cell, we hypothesize that DUB inhibition induces GPX4 degradation. Here we used palladium pyrithione complex (PdPT), a broad spectrum deubiquitinase inhibitor, to explore its cell death induction and anti-cancer effect in vitro, ex vivo, and in vivo. Mechanically, caspase activation and GPX4 protein degradation are required for PdPT-induced apoptosis and ferroptosis, respectively. Notably, PdPT-induced multiple deubiquitinase inhibition is essential for proteasomal degradation of GPX4. These findings not only identify a novel mechanism of post-translational modification of GPX4 in ferroptosis, but also suggest a potential anti-caner therapeutic strategy using Pan-DUB inhibition.
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