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Defective cytochrome c-dependent caspase activation in ovarian cancer cell lines due to diminished or absent

B B Wolf1, M Schuler, W Li

  • 1La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA. ben_wolf@liai.org

The Journal of Biological Chemistry
|June 29, 2001
PubMed

Insights

Ovarian cancer cells show reduced apoptosis due to impaired apoptotic protease-activating factor-1 (APAF-1) activity. This dysfunction in the mitochondrial apoptosis pathway may contribute to cancer development.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Apoptosis, or programmed cell death, is crucial for preventing oncogenesis.
  • The mitochondrial pathway of apoptosis involves cytochrome c release, apoptosome formation (APAF-1 oligomerization), and caspase activation.
  • Dysregulation of apoptosis is a hallmark of cancer, particularly ovarian cancer.

Purpose of the Study:

  • To investigate the role of the mitochondrial apoptosis pathway in ovarian cancer.
  • To determine if ovarian cancer cell lines exhibit resistance to cytochrome c-dependent caspase activation.
  • To identify potential mechanisms underlying apoptosis resistance in ovarian cancer.

Main Methods:

  • Utilized a cell-free system to assess cytochrome c-dependent caspase activation.
  • Analyzed cytosolic extracts from 10 ovarian cancer cell lines and normal ovarian epithelium.
  • Evaluated APAF-1 activity, expression of apoptosis-related proteins (APAF-1, caspase-9, -3, -7), and APAF-1 mutations/degradation.

Main Results:

  • All tested ovarian cancer cell lines demonstrated diminished cytochrome c-dependent caspase activation compared to normal controls.
  • Despite expressing necessary components, ovarian cancer cell lines showed reduced APAF-1 activity.
  • Diminished APAF-1 activity, potentially due to a competitive inhibitor, correlated with apoptosis resistance in some cell lines.

Conclusions:

  • Ovarian cancer cell lines exhibit impaired APAF-1 activity, contributing to resistance to apoptosis.
  • Regulation of APAF-1 activity appears to be a significant factor in apoptosis dysregulation in some ovarian cancers.
  • These findings highlight APAF-1 as a potential target for ovarian cancer therapy.

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