Cheng Feng, Dou Jintao, Yang Yi, Sun Shaojie, Chen Ruiqi, Zhang Zhijian, Wei Huijun, Li Jianhui, Wu Zhihao
Research laboratory of Tumor Microenvironment, Wannan Medical College, 241001, Wuhu, China.
School of Anesthesiology, Wannan Medical College, 241001, Wuhu, China.
Cell Death Discov. 2023 May 15;9(1):165. doi: 10.1038/s41420-023-01463-5.
Ferroptosis is a newly defined non-apoptotic programmed cell death resulting from the accumulation of lipid peroxides. Whether ferroptosis plays any role in chemotherapy remains to be established. Here, we reported that ferroptosis represents a part of the chemotherapeutic drug etoposide-induced cell death response in Small Cell Lung Cancer (SCLC) cells and adaptive signaling molecule lactate protects Non-Small Cell Lung Cancer (NSCLC) from etoposide-induced ferroptosis. Lactate derived from metabolic reprogramming increases the expression of glutathione peroxidase 4 (GPX4) to promote ferroptosis resistance in NSCLC. Furthermore, we identified E3-ubiquitin ligase NEDD4L as a major regulator of GPX4 stability. Mechanistically, Lactate increases mitochondrial ROS generation and drives activation of the p38-SGK1 pathway, which attenuates the interaction of NEDD4L with GPX4 and subsequent ubiquitination and degradation of GPX4. Our data implicated the role of ferroptosis in chemotherapeutic resistance and identified a novel post-translational regulatory mechanism for the key Ferroptosis mediator GPX4.
铁死亡是一种新定义的非凋亡程序性细胞死亡，由脂质过氧化物的积累引起。铁死亡在化疗中是否起作用仍有待确定。在此，我们报道铁死亡是化疗药物依托泊苷诱导小细胞肺癌（SCLC）细胞死亡反应的一部分，而适应性信号分子乳酸可保护非小细胞肺癌（NSCLC）免受依托泊苷诱导的铁死亡。代谢重编程产生的乳酸增加了谷胱甘肽过氧化物酶4（GPX4）的表达，以促进NSCLC中的铁死亡抗性。此外，我们确定E3泛素连接酶NEDD4L是GPX4稳定性的主要调节因子。从机制上讲，乳酸增加线粒体ROS生成并驱动p38-SGK1途径的激活，这减弱了NEDD4L与GPX4的相互作用以及随后GPX4的泛素化和降解。我们的数据表明了铁死亡在化疗耐药中的作用，并确定了关键铁死亡介质GPX4的一种新的翻译后调控机制。
