Department of Pharmaceutical Science, China Medical University-The Queen's University of Belfast Joint College, Shenyang, China.
School of Life Sciences, China Medical University, Shenyang, China.
FEBS Open Bio. 2022 Jun;12(6):1197-1205. doi: 10.1002/2211-5463.13393. Epub 2022 Mar 18.
Ferroptosis is type of programmed cell death, which is known to be involved in certain cancers. Notch3 signaling is reported to be involved in the tumorigenesis of non-small-cell lung cancer (NSCLC) and regulates iron metabolism, lipid synthesis, and oxidative stress in some tissues. However, whether Notch3 signaling regulates ferroptosis is unclear. In this study, we found that ferroptosis inhibitors, ferrostatin-1 and liproxstatin-1, protected against cell death induced by Notch3 knockdown and that Notch3 knockdown initiated ferroptosis in NSCLC cells by increasing reactive oxygen species (ROS) levels, lipid peroxidation, and Fe levels, accompanied by downregulation of glutathione peroxidase 4 (GPX4) and peroxiredoxin6 (PRDX6). Conversely, Notch3 intracellular domain overexpression suppressed erastin-induced ferroptosis, which was synergistically enhanced by MJ33 in H1299 cells via a decrease in ROS levels and lipid peroxidation, accompanied by upregulation of GPX4 and PRDX6. Moreover, Notch3 knockdown decreased tumorigenesis in vivo with downregulation of GPX4 and PRDX6. In summary, here we have identified Notch3 as a potential negative regulator of ferroptosis in NSCLC.
铁死亡是一种程序性细胞死亡，已知其参与了某些癌症的发生。有报道称 Notch3 信号参与了非小细胞肺癌（NSCLC）的肿瘤发生，并调节某些组织中的铁代谢、脂质合成和氧化应激。然而，Notch3 信号是否调节铁死亡尚不清楚。在本研究中，我们发现铁死亡抑制剂 ferrostatin-1 和 liproxstatin-1 可防止 Notch3 敲低诱导的细胞死亡，而 Notch3 敲低通过增加活性氧（ROS）水平、脂质过氧化和 Fe 水平引发 NSCLC 细胞的铁死亡，同时下调谷胱甘肽过氧化物酶 4（GPX4）和过氧化物酶 6（PRDX6）。相反，Notch3 细胞内结构域过表达通过降低 ROS 水平和脂质过氧化协同增强 erastin 诱导的铁死亡，同时上调 GPX4 和 PRDX6。此外，Notch3 敲低通过下调 GPX4 和 PRDX6 降低体内肿瘤发生。总之，我们在这里鉴定出 Notch3 是 NSCLC 中铁死亡的潜在负调控因子。
