Journal
SCIENCE ADVANCES
Volume 5, Issue 7, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aau9433
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Funding
- Stiftung Kinderkrebsforschung Schweiz
- MAM-Fonds of the Children's Research Centre of the University Children's Hospital Zurich
- Empiris Foundation
- clinical research focus program human hemato-lymphatic diseases of the University of Zurich
- Swiss Cancer League [KFS 3609-02-2015, KFS-4384-022018]
- Novartis Foundation for Biomedical Research
- Swiss National Science Foundation (SNF) [310030-133108]
- Canadian Institutes of Health Research (CIHR)
- Iten-Kohaut Stiftung
- Fondation Panacee
- Swiss National Science Foundation (SNF) [310030_133108] Funding Source: Swiss National Science Foundation (SNF)
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Apoptosis is a complex multi-step process driven by caspase-dependent proteolytic cleavage cascades. Dysregulation of apoptosis promotes tumorigenesis and limits the efficacy of chemotherapy. To assess the complex interactions among caspases during apoptosis, we disrupted caspase-8, -9, -3, -7, or -6 and combinations thereof, using CRISPR-based genome editing in living human leukemia cells. While loss of apical initiator caspase-8 or -9 partially blocked extrinsic or intrinsic apoptosis, respectively, only combined loss of caspase-3 and -7 fully inhibited both apoptotic pathways, with no discernible effect of caspase-6 deficiency alone or in combination. Caspase-3/7 double knockout cells exhibited almost complete inhibition of caspase-8 or -9 activation. Furthermore, deletion of caspase-3 and -7 decreased mitochondria! depolarization and cytochrome c release upon apoptosis activation. Thus, activation of effector caspase-3 or -7 sets off explosive feedback amplification of upstream apoptotic events, which is a key feature of apoptotic signaling essential for efficient apoptotic cell death.
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