Timosaponin AIII promotes non-small-cell lung cancer ferroptosis through targeting and facilitating HSP90 mediated GPX4 ubiquitination and degradation

作者：Cong Zhou, Ting Yu, Rui Zhu, Junjie Lu, Xiaohu Ouyang, Zili Zhang, Qianyun Chen, Junyi Li, Jing Cui, Feng Jiang, Kim Yun Jin, Alexey Sarapultsev, Fangfei Li, Ge Zhang, Shanshan Luo, Desheng Hu · 发表于：International Journal of Biological Sciences · 年份：2023 · DOI：10.7150/ijbs.77979 · 被引用次数：178 · 研究领域：Ferroptosis and cancer prognosis、Cancer, Lipids, and Metabolism、Cancer-related molecular mechanisms research

Timosaponin AIII (Tim-AIII), a steroid saponin, exhibits strong anticancer activity in a variety of cancers, especially breast cancer and liver cancer.However, the underlying mechanism of the effects of Tim-AIII-mediated anti-lung cancer effects remain obscure.In this study, we showed that Tim-AIII suppressed cell proliferation and migration, induced G2/M phase arrest and ultimately triggered cell death of non-small cell lung cancer (NSCLC) cell lines accompanied by the release of reactive oxygen species (ROS) and iron accumulation, malondialdehyde (MDA) production, and glutathione (GSH) depletion.Interestingly, we found that Tim-AIII-mediated cell death was reversed by ferroptosis inhibitor ferrostatin-1 (Fer-1).Meanwhile, the heat shock protein 90 (HSP90) was predicted and verified as the direct binding target of Tim-AIII by SwissTargetPrediction (STP) and surface plasmon resonance (SPR) assay.Further study showed that Tim-AIII promoted HSP90 expression and Tim-AIII induced cell death was blocked by the HSP90 inhibitor tanespimycin, indicating that HSP90 was the main target of Tim-AIII to further trigger intracellular events.Mechanical analysis revealed that the Tim-AIII-HSP90 complex further targeted and degraded glutathione peroxidase 4 (GPX4), and promoted the ubiquitination of GPX4, as shown by an immunoprecipitation, degradation and in vitro ubiquitination assay.In addition, Tim-AIII inhibited cell proliferation, induced cell death, led to ROS and iron accumulation, MD...