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Updated: Jun 14, 2026
08:47
Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
Published on: March 5, 2018
Mutant PIK3CA licenses TRAIL and CD95L to induce non-apoptotic caspase-8-mediated ROCK activation
M Ehrenschwender1, D Siegmund, A Wicovsky
1Department of Internal Medicine II, University Hospital Würzburg, Germany.
Cell Death and Differentiation
|April 10, 2010
Summary
Mutant PIK3CA promotes tumor growth by hijacking cell death pathways. This activates caspase-8 without apoptosis, driving invasion and amoeboid shape changes, converting tumor surveillance into promotion.
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Signaling Pathways
Background:
- Constitutively active PI3K catalytic subunit alpha (PIK3CA) mutations are common in cancer.
- PIK3CA signaling can impact apoptosis and cell behavior.
- Death receptor signaling pathways, including TRAIL and CD95L, are involved in apoptosis and immune surveillance.
Purpose of the Study:
- To investigate how constitutively active PIK3CA affects apoptosis induction and downstream signaling.
- To elucidate the role of caspase-8 in PIK3CA-mediated cellular changes.
- To identify novel mechanisms by which PIK3CA promotes tumor progression.
Main Methods:
- Utilized cells expressing mutant PIK3CA.
- Stimulated cells with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95L.
- Assessed apoptosis induction, caspase-8 activation, nuclear factor kappaB (NFkappaB) activation, cell morphology, and invasion.
- Performed caspase-8 knockdown and FLIP-S expression experiments.
- Investigated cleavage of rho-associated, coiled-coil containing protein kinase 1 (ROCK1).
Main Results:
- Mutant PIK3CA allowed caspase-8 activation without apoptosis execution.
- TRAIL and CD95L induced NFkappaB activation, invasion, and amoeboid morphology in mutant PIK3CA cells.
- NFkappaB activation and amoeboid shape changes were inhibited by caspase-8 knockdown or FLIP-S.
- Cell morphology changes required caspase-8 activity, but not caspase-3.
- Identified caspase-8-mediated, caspase-3-independent cleavage of ROCK1, promoting amoeboid shape and invasiveness.
Conclusions:
- Mutated PIK3CA redirects death receptor signaling from tumor surveillance to tumor promotion.
- Caspase-8 activation, independent of apoptosis, drives cancer cell invasion and morphological changes.
- Caspase-8-mediated ROCK1 cleavage is a novel mechanism for enhanced cancer cell invasiveness.
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