Activation of caspase-3-dependent and -independent pathways during 7-ketocholesterol- and 7β-hydroxycholesterol-induced cell death: A morphological and biochemical study

On treatment with 7‐ketocholesterol (7‐keto) or 7β‐hydroxycholesterol (7β‐OH), which are major oxysterols in atherosclerotic plaques, the simultaneous identification of oncotic and apoptotic cells suggests that these compounds activate different metabolic pathways leading to various modes of cell de...

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Bibliographic Details
Published in:Journal of biochemical and molecular toxicology 2005-11, Vol.19 (5), p.311-326
Main Authors: Prunet, Céline, Lemaire-Ewing, Stéphanie, Ménétrier, Franck, Néel, Dominique, Lizard, Gérard
Format: Article
Language:English
Subjects:
AIF
Apoptosis
Bid
Caspases
Cell Death
Endo G
ICAD
Oxysterols
PARP
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Summary:On treatment with 7‐ketocholesterol (7‐keto) or 7β‐hydroxycholesterol (7β‐OH), which are major oxysterols in atherosclerotic plaques, the simultaneous identification of oncotic and apoptotic cells suggests that these compounds activate different metabolic pathways leading to various modes of cell death. With U937, MCF‐7 (caspase‐3 deficient), MCF‐7/c3 cells (stably transfected with caspase‐3), we demonstrate that caspase‐3 is essential for caspase‐9, ‐7, ‐8 activation, for Bid degradation mediating mitochondrial cytochrome c release, for cleavage of poly(ADP‐ribose) polymerase and inhibitor of the caspase‐activated deoxyribonuclease, and, at least in part, for internucleosomal DNA fragmentation. The crucial role of caspase‐3 was supported by the use of z‐VAD‐fmk and z‐DEVD‐fmk, which abolished apoptosis and the associated events. However, inactivation or lack of caspase‐3 did not inhibit 7‐keto‐ and 7β‐OH‐induced cell death characterized by staining with propidium iodide, loss of mitochondrial potential. The mitochondrial release of apoptosis‐inducing factor and endonuclease G was independent of the caspase‐3 status, which conversely played major roles in the morphological aspects of dead cells. We conclude that caspase‐3 is essential to trigger 7‐keto‐ and 7β‐OH‐induced apoptosis, that these oxysterols simultaneously activate caspase‐3‐dependent and/or ‐independent modes of cell death. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:311–326, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20096
ISSN:1095-6670
1099-0461
DOI:10.1002/jbt.20096