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Sublethal cytochrome c release generates drug-tolerant persister cells
Halime Kalkavan1, Mark J Chen1, Jeremy C Crawford1
1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cell
|September 2, 2022
Summary
Drug-tolerant persister cells evade cancer therapy. Sublethal mitochondrial damage and cytochrome c release trigger a stress response, creating these persister cells, which are vulnerable to ferroptosis.
Area of Science:
- Cell Biology
- Cancer Research
- Molecular Oncology
Background:
- Drug-tolerant persister cells (persisters) are a significant obstacle in cancer treatment, evading apoptosis induced by therapies.
- Understanding the mechanisms behind persister cell formation is crucial for developing more effective cancer therapies.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the generation of drug-tolerant persister cells.
- To identify key signaling pathways involved in persister cell survival and their vulnerabilities.
Main Methods:
- Utilized pro-apoptotic BH3 mimetics to induce persister cell formation in cancer models.
- Investigated mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release.
- Analyzed the roles of the integrated stress response (ISR), heme-regulated inhibitor (HRI) kinase, and ATF4 in persister cell generation.
Main Results:
- Cells surviving BH3 mimetic treatment exhibited a persister phenotype, including in vivo colonization and metastasis.
- Sublethal MOMP and holocytochrome c release were essential for generating persister cells.
- Persister cell generation was independent of apoptosome and caspase activation but required cytosolic cytochrome c, HRI kinase, ISR, and ATF4.
Conclusions:
- Sublethal cytochrome c release links sublethal MOMP to caspase-independent ATF4 activation, establishing a drug-tolerant persister phenotype.
- Persister cells show increased sensitivity to ferroptosis induction via GPX4 inhibition.
- These findings reveal a novel pathway for persister cell generation and suggest potential therapeutic strategies targeting this mechanism.
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