Department of Experimental Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Graduate Field of Biomedical and Biological Sciences, Cornell University, Ithaca, NY, USA.
Nat Commun. 2021 Mar 11;12(1):1589. doi: 10.1038/s41467-021-21841-w.
Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear. In this study, we perform integrated proteomic and functional analyses to reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis, but also GPX4 protein synthesis. Mechanistically, we find that cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the Rag-mTORC1-4EBP signaling axis. We show that pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment.
谷胱甘肽过氧化物酶 4（GPX4）利用谷胱甘肽（GSH）来解毒脂质过氧化，并在抑制铁死亡中发挥重要作用。作为一种硒蛋白，GPX4 蛋白的合成效率非常低，且能量成本高。细胞如何协调 GPX4 的合成与营养物质的可用性仍然不清楚。在这项研究中，我们进行了综合蛋白质组学和功能分析，揭示了 SLC7A11 介导的胱氨酸摄取不仅促进 GSH 合成，还促进 GPX4 蛋白合成。在机制上，我们发现半胱氨酸激活了 mechanistic/mammalian target of rapamycin complex 1（mTORC1），并通过 Rag-mTORC1-4EBP 信号轴至少部分地促进 GPX4 蛋白合成。我们表明，mTORC1 的药理学抑制降低了 GPX4 蛋白水平，使癌细胞对铁死亡敏感，并与铁死亡诱导剂协同作用，抑制体内患者来源的异种移植肿瘤生长。总之，我们的结果揭示了一种调节机制，可协调 GPX4 蛋白合成与半胱氨酸的可用性，并表明在癌症治疗中使用 mTORC1 抑制剂和铁死亡诱导剂的联合治疗。
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