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Sci Adv. 2019 Jul 31;5(7):eaau9433. doi: 10.1126/sciadv.aau9433. eCollection 2019 Jul.

Efficient apoptosis requires feedback amplification of upstream apoptotic signals by effector caspase-3 or -7.

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Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, 8032 Zürich, Switzerland.
IQVIA Technology and Services AG Theaterstrasse 4, 4051 Basel, Switzerland.


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 mitochondrial 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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