Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
Department of Chemistry, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
Cell. 2014 Jan 16;156(1-2):317-331. doi: 10.1016/j.cell.2013.12.010.
Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death.
铁死亡是一种非细胞凋亡的细胞死亡形式，其关键调节因子仍不清楚。我们试图寻找一种共同的介质，以解释 12 种诱导铁死亡的小分子的致死性。我们使用靶向代谢组学分析发现，谷胱甘肽耗竭会导致谷胱甘肽过氧化物酶 (GPXs) 在一类化合物的作用下失活，并且利用化学蛋白质组学策略发现，GPX4 会被第二类化合物直接抑制。GPX4 的过表达和敲低调节了 12 种铁死亡诱导剂的致死性，但对其他 11 种具有其他致死机制的化合物没有影响。此外，两种代表性的铁死亡诱导剂可预防异种移植小鼠肿瘤模型中的肿瘤生长。在 177 种癌细胞系中的敏感性分析表明，弥漫性大 B 细胞淋巴瘤和肾细胞癌对 GPX4 调控的铁死亡特别敏感。因此，GPX4 是铁死亡性癌细胞死亡的一个必需调节因子。
