Aspirin Induces Apoptosis through Release of Cytochrome c from Mitochondria

Nonsteroidal anti-inflammatory drugs (NSAID) reduce the risk for cancer, due to their anti proliferative and apoptosis-inducing effects. A critical pathway for apoptosis involves the release of cytochrome c from mitochondria, which then interacts with Apaf-1 to activate caspase proteases that orches...

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Bibliographic Details
Published in:Neoplasia (New York, N.Y.) N.Y.), 2000, Vol.2 (6), p.505-513
Main Authors: Zimmermann, Katja C., Waterhouse, Nigel J., Goldstein, Joshua C., Schuler, Martin, Green, Douglas R.
Format: Article
Language:English
Subjects:
Amino Acid Chloromethyl Ketones - pharmacology
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
apoptosis
Apoptosis - drug effects
Apoptotic Protease-Activating Factor 1
aspirin
Aspirin - pharmacology
bcl-2-Associated X Protein
Blotting, Western
Caspase Inhibitors
Caspases - metabolism
Cysteine Proteinase Inhibitors - pharmacology
cytochrome c
Cytochrome c Group - metabolism
Flow Cytometry
Green Fluorescent Proteins
HeLa Cells
Humans
Luminescent Proteins - metabolism
Microscopy, Confocal
mitochondria
Mitochondria - drug effects
Mitochondria - enzymology
NSAID
Protein Transport
Proteins - metabolism
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-bcl-2 - metabolism
Transfection
Tumor Cells, Cultured
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Summary:Nonsteroidal anti-inflammatory drugs (NSAID) reduce the risk for cancer, due to their anti proliferative and apoptosis-inducing effects. A critical pathway for apoptosis involves the release of cytochrome c from mitochondria, which then interacts with Apaf-1 to activate caspase proteases that orchestrate cell death. In this study we found that treatment of a human cancer cell line with aspirin induced caspase activation and the apoptotic cell morphology, which was blocked by the caspase inhibitor zVAD-fmk. Further analysis of the mechanism underlying this apoptotic event showed that aspirin induces translocation of Bax to the mitochondria and triggers release of cytochrome c into the cytosol. The release of cytochrome c from mitochondria was inhibited by overexpression of the antiapoptotic protein Bcl-2 and cells that lack Apaf-1 were resistant to aspirin-induced apoptosis. These data provide evidence that the release of cytochrome c is an important part of the apoptotic mechanism of aspirin.
ISSN:1476-5586
1522-8002
1476-5586
1522-8002
DOI:10.1038/sj.neo.7900120