内德4
细胞生物学
泛素
程序性细胞死亡
激活剂(遗传学)
HEK 293细胞
化学
自噬
细胞
癌细胞
癌症研究
泛素连接酶
细胞凋亡
生物
癌症
生物化学
基因
遗传学
作者
Yongfei Yang,Meiying Luo,Kexin Zhang,Jun Zhang,Ting Gao,Douglas O’ Connell,Fengping Yao,Changwen Mu,Bingyu Cai,Yuxue Shang,Wei Chen
标识
DOI:10.1038/s41467-020-14324-x
摘要
Abstract Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Erastin, the ferroptosis activator, binds to voltage-dependent anion channels VDAC2 and VDCA3, but treatment with erastin can result in the degradation of the channels. Here, the authors show that Nedd4 is induced following erastin treatment, which leads to the ubiquitination and subsequent degradation of the channels. Depletion of Nedd4 limits the protein degradation of VDAC2/3, which increases the sensitivity of cancer cells to erastin. By understanding the molecular mechanism of erastin-induced cellular resistance, we can discover how cells adapt to new molecules to maintain homeostasis. Furthermore, erastin-induced resistance mediated by FOXM1-Nedd4-VDAC2/3 negative feedback loop provides an initial framework for creating avenues to overcome the drug resistance of ferroptosis activators.
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