Notch3 regulates ferroptosis via ROS‐induced lipid peroxidation in NSCLC cells

作者：Zhikang Li, Jinyang Xiao, Mengyu Liu, Jiaqi Cui, Bowen Lian, Yuanlu Sun, Chunyan Li · 发表于：FEBS Open Bio · 年份：2022 · DOI：10.1002/2211-5463.13393 · 被引用次数：30 · 研究领域：Ferroptosis and cancer prognosis、Cancer-related molecular mechanisms research、Epigenetics and DNA Methylation

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 2+ 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.