Liu Liying, Liu Bingju, Guan Guotao, Kang Rui, Dai Yunpeng, Tang Daolin
Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
Biochem Biophys Res Commun. 2022 May 28;606:68-74. doi: 10.1016/j.bbrc.2022.03.098. Epub 2022 Mar 21.
Cyclophosphamide is an alkylating agent used to treat a variety of cancers, including leukemia. Here, we show a previously unrecognized role of cyclophosphamide in triggering the protein degradation of glutathione peroxidase 4 (GPX4), a phospholipid hydroperoxidase that protects cells from oxidative damage. Mechanistically, we found that the ubiquitin-proteasome system, but not autophagy, mediates cyclophosphamide-induced degradation of GPX4 in human leukemia cell lines. Surprisingly, cyclophosphamide-induced degradation of GPX4 leads to caspase-independent parthanatos, but not lipid peroxidation-mediated ferroptosis, through the nuclear translocation of apoptosis-inducing factor mitochondria-associated 1 (AIFM1). Consequently, the overexpression of GPX4 or the knockdown of AIFM1 limits the anticancer activity of cyclophosphamide in vitro and in xenograft tumor models. These findings establish a new framework for understanding the central role of GPX4 in blocking oxidative cell death.
环磷酰胺是一种用于治疗包括白血病在内的多种癌症的烷化剂。在此，我们展示了环磷酰胺在触发谷胱甘肽过氧化物酶4（GPX4）蛋白降解方面此前未被认识到的作用，GPX4是一种保护细胞免受氧化损伤的磷脂氢过氧化物酶。从机制上讲，我们发现泛素 - 蛋白酶体系统而非自噬介导了环磷酰胺在人白血病细胞系中诱导的GPX4降解。令人惊讶的是，环磷酰胺诱导的GPX4降解通过凋亡诱导因子线粒体相关1（AIFM1）的核转位导致不依赖半胱天冬酶的parthanatos，而非脂质过氧化介导的铁死亡。因此，GPX4的过表达或AIFM1的敲低限制了环磷酰胺在体外和异种移植肿瘤模型中的抗癌活性。这些发现为理解GPX4在阻断氧化性细胞死亡中的核心作用建立了一个新框架。
