细胞生物学
蛋白酶体
程序性细胞死亡
线粒体
生物
未折叠蛋白反应
生物化学
内质网
细胞凋亡
作者
Peter Tsvetkov,Alexandre Detappe,Kai Cai,Heather R. Keys,Zarina Brune,Weiwen Ying,Prathapan Thiru,Mairéad Reidy,Guillaume Kugener,Jordan Rossen,Mustafa Kocak,Nora Kory,Aviad Tsherniak,Sandro Santagata,Luke Whitesell,Irene M. Ghobrial,John L. Markley,Susan Lindquist,Todd R. Golub
标识
DOI:10.1038/s41589-019-0291-9
摘要
The mechanisms by which cells adapt to proteotoxic stress are largely unknown, but are key to understanding how tumor cells, particularly in vivo, are largely resistant to proteasome inhibitors. Analysis of cancer cell lines, mouse xenografts and patient-derived tumor samples all showed an association between mitochondrial metabolism and proteasome inhibitor sensitivity. When cells were forced to use oxidative phosphorylation rather than glycolysis, they became proteasome-inhibitor resistant. This mitochondrial state, however, creates a unique vulnerability: sensitivity to the small molecule compound elesclomol. Genome-wide CRISPR–Cas9 screening showed that a single gene, encoding the mitochondrial reductase FDX1, could rescue elesclomol-induced cell death. Enzymatic function and nuclear-magnetic-resonance-based analyses further showed that FDX1 is the direct target of elesclomol, which promotes a unique form of copper-dependent cell death. These studies explain a fundamental mechanism by which cells adapt to proteotoxic stress and suggest strategies to mitigate proteasome inhibitor resistance. Mitochondrial energy metabolism regulates proteotoxic stress tolerance, exposing a newly discovered sensitivity to the small molecule elesclomol, which induces FDX1-mediated, copper-dependent cell death.
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