美国圣裘德儿童研究医院Douglas R. Green课题组发现，亚致死性细胞色素c释放产生耐药性顽固细胞。相关论文发表在2022年9月1日出版的《细胞》杂志上。

研究人员表明，用促凋亡BH3模拟物治疗后存活的细胞显示出一种顽固细胞的表型，包括体内的定植和转移，以及对GPX4抑制的铁死亡敏感性增加。研究人员发现，亚致死性线粒体外膜透化（MOMP）和完整细胞色素c释放是产生顽固细胞表型的关键需求。顽固细胞的产生与细胞凋亡体的形成和caspase的激活无关，相反，细胞色素c诱导血红蛋白调节抑制剂（HRI）激酶的激活和综合应激反应（ISR）的参与，从而合成ATF4，所有这些都是顽固细胞表型所需要的。

这些研究结果显示，亚致死性细胞色素c的释放使亚致死性MOMP与caspase无关的ATF4依赖性、药物耐受性持久性表型的启动相联系。

据悉，耐药性顽固细胞在靶向和常规癌症治疗中逃避凋亡，是有效癌症治疗的一个主要非遗传障碍。

附：英文原文

Title: Sublethal cytochrome c release generates drug-tolerant persister cells

Author: Halime Kalkavan, Mark J. Chen, Jeremy C. Crawford, Giovanni Quarato, Patrick Fitzgerald, Stephen W.G. Tait, Colin R. Goding, Douglas R. Green

Issue&Volume: 2022/09/01

Abstract: Drug-tolerant persister cells (persisters) evade apoptosis upon targeted and conventionalcancer 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 displaya persister phenotype that includes colonization and metastasis in vivo and increased sensitivity toward ferroptosis by GPX4 inhibition. We found that sublethalmitochondrial outer membrane permeabilization (MOMP) and holocytochrome c release are key requirements for the generation of the persister phenotype. The generationof 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 ofthe integrated stress response (ISR) with the consequent synthesis of ATF4, all ofwhich are required for the persister phenotype. Our results reveal that sublethalcytochrome c release couples sublethal MOMP to caspase-independent initiation of an ATF4-dependent,drug-tolerant persister phenotype.

DOI: 10.1016/j.cell.2022.07.025

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00978-3