1. Academic Validation
  2. Sublethal cytochrome c release generates drug-tolerant persister cells

Sublethal cytochrome c release generates drug-tolerant persister cells

  • Cell. 2022 Sep 1;185(18):3356-3374.e22. doi: 10.1016/j.cell.2022.07.025.
Halime Kalkavan 1 Mark J Chen 1 Jeremy C Crawford 1 Giovanni Quarato 1 Patrick Fitzgerald 1 Stephen W G Tait 2 Colin R Goding 3 Douglas R Green 4
Affiliations

Affiliations

  • 1 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 2 Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK.
  • 3 Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX37DQ, UK.
  • 4 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: [email protected]
Abstract

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.

Keywords

ATF4; Bcl-2 family; GPX4; HRI; ferroptosis; persister integrated stress response.

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