Defective Cytochrome c-dependent Caspase Activation in Ovarian Cancer Cell Lines due to Diminished or Absent Apoptotic Protease Activating Factor-1 Activity

Beni B. Wolf, Martin Schuler, Wei Li, Beth Eggers-Sedlet, Wilson Lee, Pankaj Tailor, Patrick Fitzgerald, Gordon Mills, Douglas R. Green

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

Apoptosis via the mitochondrial pathway requires release of cytochrome c into the cytosol to initiate formation of an oligomeric apoptotic protease-activating factor-1 (APAF-1) apoptosome. The apoptosome recruits and activates caspase-9, which in turn activates caspase-3 and -7, which then kill the cell by proteolysis. Because inactivation of this pathway may promote oncogenesis, we examined 10 ovarian cancer cell lines for resistance to cytochrome c-dependent caspase activation using a cell-free system. Strikingly, we found that cytosolic extracts from all cell lines had diminished cytochrome c-dependent caspase activation compared with normal ovarian epithelium extracts. The resistant cell lines expressed APAF-1 and caspase-9, -3, and -7; however, each demonstrated diminished APAF-1 activity relative to the normal ovarian epithelium cell lines. A competitive APAF-1 inhibitor may account for the diminished APAF-1 activity because we did not detect dominant APAF-1 inhibitors, altered APAF-1 isoform expression, or APAF-1 deletion, degradation, or mutation. Lack of APAF-1 activity correlated in some but not all cell lines with resistance to apoptosis. These data suggest that regulation of APAF-1 activity may be important for apoptosis regulation in some ovarian cancers.

Original languageEnglish (US)
Pages (from-to)34244-34251
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number36
DOIs
StatePublished - Sep 7 2001
Externally publishedYes

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Apoptotic Protease-Activating Factor 1
Caspases
Cytochromes c
Ovarian Neoplasms
Chemical activation
Cells
Cell Line
Apoptosomes
Caspase 9
Apoptosis
Caspase 3
Epithelium
Proteolysis
Caspase 7
Cell-Free System
Cytosol

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Defective Cytochrome c-dependent Caspase Activation in Ovarian Cancer Cell Lines due to Diminished or Absent Apoptotic Protease Activating Factor-1 Activity. / Wolf, Beni B.; Schuler, Martin; Li, Wei; Eggers-Sedlet, Beth; Lee, Wilson; Tailor, Pankaj; Fitzgerald, Patrick; Mills, Gordon; Green, Douglas R.

In: Journal of Biological Chemistry, Vol. 276, No. 36, 07.09.2001, p. 34244-34251.

Research output: Contribution to journalArticle

Wolf, Beni B. ; Schuler, Martin ; Li, Wei ; Eggers-Sedlet, Beth ; Lee, Wilson ; Tailor, Pankaj ; Fitzgerald, Patrick ; Mills, Gordon ; Green, Douglas R. / Defective Cytochrome c-dependent Caspase Activation in Ovarian Cancer Cell Lines due to Diminished or Absent Apoptotic Protease Activating Factor-1 Activity. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 36. pp. 34244-34251.
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