Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31189-31197. doi: 10.1073/pnas.2017152117. Epub 2020 Nov 23.
Ferroptosis, a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various signaling pathways related to cancer. In this study, we found that activating mutation of phosphatidylinositol 3-kinase (PI3K) or loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function, highly frequent events in human cancer, confers ferroptosis resistance in cancer cells, and that inhibition of the PI3K-AKT-mTOR signaling axis sensitizes cancer cells to ferroptosis induction. Mechanistically, this resistance requires sustained activation of mTORC1 and the mechanistic target of rapamycin (mTOR)C1-dependent induction of sterol regulatory element-binding protein 1 (SREBP1), a central transcription factor regulating lipid metabolism. Furthermore, stearoyl-CoA desaturase-1 (SCD1), a transcriptional target of SREBP1, mediates the ferroptosis-suppressing activity of SREBP1 by producing monounsaturated fatty acids. Genetic or pharmacologic ablation of SREBP1 or SCD1 sensitized ferroptosis in cancer cells with PI3K-AKT-mTOR pathway mutation. Conversely, ectopic expression of SREPB1 or SCD1 restored ferroptosis resistance in these cells, even when mTORC1 was inhibited. In xenograft mouse models for PI3K-mutated breast cancer and PTEN-defective prostate cancer, the combination of mTORC1 inhibition with ferroptosis induction resulted in near-complete tumor regression. In conclusion, hyperactive mutation of PI3K-AKT-mTOR signaling protects cancer cells from oxidative stress and ferroptotic death through SREBP1/SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with ferroptosis induction shows therapeutic promise in preclinical models.
铁死亡是一种依赖铁的脂质过氧化的受调控的细胞坏死形式，受到细胞代谢、氧化还原平衡和与癌症相关的各种信号通路的调节。在这项研究中，我们发现，在人类癌症中高频发生的磷酸肌醇 3-激酶（PI3K）的激活突变或磷酸酶和张力蛋白同源物缺失于染色体 10（PTEN）的功能丧失赋予了癌细胞对铁死亡的抗性，并且抑制 PI3K-AKT-mTOR 信号通路使癌细胞对铁死亡诱导敏感。从机制上讲，这种抗性需要持续激活 mTORC1 和机械靶点雷帕霉素（mTOR）C1 依赖性固醇调节元件结合蛋白 1（SREBP1）的诱导，SREBP1 是调节脂质代谢的核心转录因子。此外，硬脂酰辅酶 A 去饱和酶-1（SCD1）是 SREBP1 的转录靶点，通过产生单不饱和脂肪酸来介导 SREBP1 的铁死亡抑制活性。SREBP1 或 SCD1 的基因或药理学缺失使具有 PI3K-AKT-mTOR 途径突变的癌细胞对铁死亡敏感。相反，SREBP1 或 SCD1 的异位表达即使在抑制 mTORC1 时也恢复了这些细胞的铁死亡抗性。在携带 PI3K 突变的乳腺癌和 PTEN 缺陷的前列腺癌的异种移植小鼠模型中，mTORC1 抑制与铁死亡诱导的联合治疗导致肿瘤几乎完全消退。总之，PI3K-AKT-mTOR 信号的过度活跃突变通过 SREBP1/SCD1 介导的脂肪生成来保护癌细胞免受氧化应激和铁死亡死亡，并且 mTORC1 抑制与铁死亡诱导的联合治疗在临床前模型中显示出治疗潜力。
