Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK.
Cell. 2022 Sep 1;185(18):3356-3374.e22. doi: 10.1016/j.cell.2022.07.025.
Drug-tolerant persister cells (persisters) evade apoptosis upon targeted and conventional cancer therapies and represent a major non-genetic barrier to effective cancer treatment. Here, we show that cells that survive treatment with pro-apoptotic BH3 mimetics display a persister phenotype that includes colonization and metastasis in vivo and increased sensitivity toward ferroptosis by GPX4 inhibition. We found that sublethal mitochondrial outer membrane permeabilization (MOMP) and holocytochrome c release are key requirements for the generation of the persister phenotype. The generation of persisters is independent of apoptosome formation and caspase activation, but instead, cytosolic cytochrome c induces the activation of heme-regulated inhibitor (HRI) kinase and engagement of the integrated stress response (ISR) with the consequent synthesis of ATF4, all of which are required for the persister phenotype. Our results reveal that sublethal cytochrome c release couples sublethal MOMP to caspase-independent initiation of an ATF4-dependent, drug-tolerant persister phenotype.
耐药物的持久细胞(持久细胞)在针对癌症的靶向治疗和常规治疗中逃避细胞凋亡,是有效癌症治疗的一个主要的非遗传障碍。在这里,我们发现,在用促凋亡 BH3 模拟物治疗后存活的细胞表现出持久细胞表型,包括体内定植和转移,并对 GPX4 抑制的铁死亡更敏感。我们发现,亚致死性线粒体外膜通透化(MOMP)和全细胞色素 c 释放是产生持久细胞表型的关键要求。持久细胞的产生不依赖于凋亡体的形成和半胱天冬酶的激活,而是细胞质细胞色素 c 诱导血红素调节抑制剂(HRI)激酶的激活和整合应激反应(ISR)的参与,随之而来的是 ATF4 的合成,所有这些都是持久细胞表型所必需的。我们的研究结果表明,亚致死细胞色素 c 的释放将亚致死性 MOMP 与半胱天冬酶非依赖性 ATF4 依赖性耐药物持久细胞表型的起始偶联起来。