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 B. Mills, Douglas R. Green

    Research output: Contribution to journalArticle

    105 Scopus citations

    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

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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