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08:47

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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
PubMed

Insights

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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