Sublethal cytochrome c release generates drug-tolerant persister cells

Kalkavan, H., Chen, M. J., Crawford, J. C., Quarato, G., Fitzgerald, P., Tait, S. W.G. , Goding, C. R. and Green, D. R. (2022) Sublethal cytochrome c release generates drug-tolerant persister cells. Cell, 185(18), 3356-3374.e22. (doi: 10.1016/j.cell.2022.07.025) (PMID:36055199)

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.

• Item Type: Articles
• Additional Information: This work was supported by ALSAC (SJCRH), the US National Cancer Institute grant R35 CA231620 to D.R.G., and the German Research Foundation (DFG, KA 4830/1-1) to H.K.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Tait, Professor Stephen
• Authors: Kalkavan, H., Chen, M. J., Crawford, J. C., Quarato, G., Fitzgerald, P., Tait, S. W.G., Goding, C. R., and Green, D. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell
• Publisher: Elsevier (Cell Press)
• ISSN: 0092-8674
• ISSN (Online): 1097-4172
• Published Online: 01 September 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Cell 185(18):3356-3374.e22
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher