Wu Ke, Yan Meisi, Liu Tong, Wang Zheng, Duan Yuran, Xia Yan, Ji Guimei, Shen Yuli, Wang Lei, Li Lin, Zheng Peixiang, Dong Bofei, Wu Qingang, Xiao Liwei, Yang Xueying, Shen Haochen, Wen Ting, Zhang Jingjing, Yi Jinfeng, Deng Yuhan, Qian Xu, Ma Leina, Fang Jing, Zhou Qin, Lu Zhimin, Xu Daqian
Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
School of Basic Medical Sciences, Harbin Medical University, Harbin, China.
Nat Cell Biol. 2023 May;25(5):714-725. doi: 10.1038/s41556-023-01133-9. Epub 2023 May 8.
Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth factor 1 receptor signalling phosphorylates creatine kinase B (CKB) T133, reduces metabolic activity of CKB and increases CKB binding to glutathione peroxidase 4 (GPX4). Importantly, CKB acts as a protein kinase and phosphorylates GPX4 S104. This phosphorylation prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumour growth in mice. In addition, the levels of GPX4 are positively correlated with the phosphorylation levels of CKB T133 and GPX4 S104 in human hepatocellular carcinoma specimens and associated with poor prognosis of patients with hepatocellular carcinoma. These findings reveal a critical mechanism by which tumour cells counteract ferroptosis by non-metabolic function of CKB-enhanced GPX4 stability and underscore the potential to target the protein kinase activity of CKB for cancer treatment.
受体蛋白激酶的激活在各种癌症中普遍存在，但其对铁死亡的影响尚不清楚。在此，我们证明胰岛素样生长因子1受体信号激活的AKT使肌酸激酶B（CKB）的T133位点磷酸化，降低CKB的代谢活性，并增加CKB与谷胱甘肽过氧化物酶4（GPX4）的结合。重要的是，CKB作为一种蛋白激酶，使GPX4的S104位点磷酸化。这种磷酸化阻止了热休克蛋白70（HSC70）与GPX4的结合，从而消除了伴侣介导的自噬对GPX4的降解调节，减轻了铁死亡并促进了小鼠肿瘤的生长。此外，在人类肝细胞癌标本中，GPX4的水平与CKB的T133位点和GPX4的S104位点的磷酸化水平呈正相关，并且与肝细胞癌患者的不良预后相关。这些发现揭示了一种关键机制，即肿瘤细胞通过CKB增强GPX4稳定性的非代谢功能来对抗铁死亡，并强调了靶向CKB的蛋白激酶活性用于癌症治疗的潜力。
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