ATM激酶介导NCOA4磷酸化参与铁死亡调节的研究

铁死亡是近年来发现的一种新型细胞死亡，依赖于游离铁介导的脂质过氧化，特异性诱导铁死亡可杀伤肿瘤细胞，为未来肿瘤治疗提供了理想靶标。近年来发现多种蛋白及代谢过程与铁死亡紧密相关，但铁死亡上游调节信号仍缺乏深入研究。应用激酶抑制剂筛选实验我们发现ATM抑制剂可显著抑制铁死亡，ATM敲除细胞对铁死亡不再敏感；铁死亡过程中ATM被激活，介导铁蛋白自噬受体NCOA4的磷酸化并参与调节铁蛋白自噬。这些研究初步表明ATM是一个关键的铁死亡上游调控激酶，其通过磷酸化NCOA4调节铁蛋白自噬并最终调控铁死亡。基于此，本项目将综合多种ATM抑制剂及ATM敲除或突变细胞，深入研究ATM在铁死亡中的关键调控作用，解析其磷酸化NCOA4调节铁蛋白自噬及铁死亡的分子细节，进而以裸鼠成瘤模型探索ATM调节的铁死亡在结直肠癌治疗中的潜在应用。研究结果将拓展对铁死亡上游调控机制的认识，并为结直肠癌的治疗提供新的思考方向。

Ferroptosis is a newly characterized form of regulated cell death, which is initiated by free iron mediated lethal accumulation of lipid peroxidation. It is widely considered that targeted induction of ferroptosis is a highly potential therapeutic strategy for cancer treatment by triggering cytotoxicity of cancer cells. Increasing researches have elaborated a series of proteins and metabolic processes involved in ferroptosis execution. However, the upstream regulatory circuits have rarely been investigated. Here by performing a kinase inhibitor screening assay, we found that the ATM kinase inhibitor can significantly suppress ferroptosis in mammalian cells. Additionally, ATM knockout cells are markedly resistant to the Erastin or RSL3 induced ferroptosis. Besides, ATM kinase is activated in response to ferroptotic stimuli. The activated ATM kinase could mediate the phosphorylation of the ferritinophagy receptor NCOA4, thus modulate ferritinophagy execution for ferritin turnover and free iron release. Altogether, the current study suggests that ATM kinase is a newly characterized regulator for ferroptosis via phosphorylating NCOA4 and regulating ferritinophagy. Based on these results, in this project, we will focus on dissecting the critical function of ATM kinase in ferroptosis regulation, and elaborating the molecular detail of ATM kinase in modulating ferritinophagy and ferroptosis via phosphorylating NCOA4, by utilizing different ATM inhibitors and several ATM depleted or mutated cells. In addition, we are also committed to exploring the potential application of ATM mediated ferroptosis in the treatment of colorectal cancer by using a xenograft tumor model. This project will strengthen the understanding for the upstream regulatory signaling of ferroptosis execution, and provide a potential strategy for therapeutic intervention of colorectal cancer.