Daunorubicin- and Ara-C-induced interphasic apoptosis of human type II leukemia cells is caspase-8-independent

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Published on: March 5, 2018

Anne-Dominique Terrisse1, Christine Bezombes, Sandra Lerouge

  • 1Institut National de la Santé et de la Recherche Médicale E9910, Institut Claudius Régaud, 20 rue Pont St Pierre, 31052 Toulouse, France.

Biochimica Et Biophysica Acta
|October 19, 2002
PubMed

Insights

Drug-induced apoptosis in leukemia cells is initiated by ceramide generation, not caspase-8 cleavage. This finding clarifies the early signaling events in Type II leukemic cells, impacting cancer research.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Interphasic apoptosis in leukemia involves complex intracellular signaling pathways.
  • The precise initiating event for drug-induced apoptosis in Type II cells remains unclear, with both ceramide generation and procaspase-8 cleavage proposed as early steps.

Purpose of the Study:

  • To determine if procaspase-8 cleavage is essential for initial ceramide generation and rapid interphasic apoptosis.
  • To investigate the chronological order of ceramide generation and caspase-8 cleavage induced by daunorubicin (DNR) and 1-beta-D-arabinofuranosylcytosine (Ara-C).

Main Methods:

  • Investigated chronological ordering of ceramide generation and caspase-8 cleavage in U937 cells treated with DNR and Ara-C.
  • Evaluated the impact of DNR and Ara-C on ceramide generation and apoptosis in wild-type Jurkat cells and Jurkat clones mutated for caspase-8 and Fas-associated death domain.

Main Results:

  • Both DNR and Ara-C induced early ceramide generation (5-20 min) and interphasic apoptosis in all tested cell models.
  • Caspase-8 cleavage was observed much later (4.5 h) and only in DNR-treated cells; neither drug induced caspase-8 activation.
  • These findings indicate that caspase-8 cleavage is not required for the initial ceramide-mediated apoptotic pathway.

Conclusions:

  • Procaspase-8 cleavage is not a requisite event for the initiation of drug-induced ceramide-mediated interphasic apoptosis in human Type II leukemic cells.
  • Ceramide generation is the proximal initiating event in this apoptotic pathway, preceding caspase-8 involvement.

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