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Paclitaxel-induced apoptosis in BJAB cells proceeds via a death receptor-independent, caspases-3/-8-driven

Clarissa von Haefen1, Thomas Wieder, Frank Essmann

  • 1Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, University of Berlin, Germany.

Oncogene
|April 18, 2003
PubMed

Insights

This study reveals a death receptor-independent amplification loop involving caspases-3 and -8, crucial for optimal cytochrome c release and cell death during paclitaxel-induced apoptosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Caspase-8 is a known effector of death-receptor-mediated apoptosis.
  • Previous work indicated caspase-8 can activate independently of death receptors, downstream of caspase-3.
  • The precise role of caspase-8 in mitochondrial apoptosis pathways remained unclear.

Purpose of the Study:

  • To investigate the role of caspases-3 and -8 in a death receptor-independent amplification loop.
  • To elucidate the mechanism of paclitaxel (Taxol)-induced apoptosis.
  • To determine the regulation of cytochrome c and Smac release from mitochondria.

Main Methods:

  • Utilized paclitaxel to induce apoptosis in cell models.
  • Employed specific caspase-3 (zDEVD-fmk) and caspase-8 (zIETD-fmk) inhibitors.
  • Used a dominant-negative FADD mutant (FADD-DN) to assess death receptor pathway involvement.
  • Overexpressed cytokine response modifier A (CrmA) in BJAB cells.

Main Results:

  • Caspases-3 and -8 mediate a mitochondrial amplification loop essential for optimal cytochrome c release, mitochondrial permeability transition, and paclitaxel-induced cell death.
  • Smac release from mitochondria occurred independently of cytochrome c release.
  • Inhibition of caspases-3 or -8 significantly reduced paclitaxel-induced cell death.
  • FADD-DN did not affect apoptosis signaling, excluding a role for death receptors in this loop.
  • Experiments with CrmA corroborated the inhibitor findings.

Conclusions:

  • Optimal mitochondrial activation, cytochrome c release, and drug-induced apoptosis necessitate a caspase-3 and -8-dependent mitochondrial amplification loop.
  • This study provides the first in vivo evidence of death receptor-independent caspase-8 autoprocessing.
  • Smac release is regulated separately from cytochrome c release during apoptosis.

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