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Sci. STKE, 24 October 2006
Vol. 2006, Issue 358, p. pe44
[DOI: 10.1126/stke.3582006pe44]

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Caspase Inhibitors Promote Alternative Cell Death Pathways

Peter Vandenabeele*, Tom Vanden Berghe, and Nele Festjens

Molecular Signalling and Cell Death Unit, Department for Molecular Biomedical Research, Flanders Interuniversity Institute of Biotechnology (VIB) and Ghent University, Fiers-Schell-Van Montagu Building, Technologiepark 927, B-9052 Ghent, Belgium.

Abstract: The use of caspase inhibitors has revealed the existence of alternative backup cell death programs for apoptosis. The broad-spectrum caspase inhibitor zVAD-fmk modulates the three major types of cell death. Addition of zVAD-fmk blocks apoptotic cell death, sensitizes cells to necrotic cell death, and induces autophagic cell death. Several studies have shown a crucial role for the kinase RIP1 and the adenosine nucleotide translocator (ANT)–cyclophilin D (CypD) complex in necrotic cell death. The underlying mechanism of zVAD-fmk–mediated sensitization to necrotic cell death involves the inhibition of caspase-8–mediated proteolysis of RIP1 and disturbance of the ANT-CypD interaction. RIP1 is also involved in autophagic cell death. Caspase inhibitors and knockdown studies have revealed negative roles for catalase and caspase-8 in autophagic cell death. The positive role of RIP1 and the negative role of caspase-8 in both necrotic and autophagic cell death suggest that the pathways of these two types of cell death are interconnected. Necrotic cell death represents a rapid cellular response involving mitochondrial reactive oxygen species (ROS) production, decreased adenosine triphosphate concentration, and other cellular insults, whereas autophagic cell death first starts as a survival attempt by cleaning up ROS-damaged mitochondria. However, when this process occurs in excess, autophagy itself becomes cytotoxic and eventually leads to autophagic cell death. A better understanding of the molecular mechanisms of these alternative cell death pathways may provide therapeutic tools to combat cell death associated with neurodegenerative diseases, ischemia-reperfusion pathologies, and infectious diseases, and may also facilitate the development of alternative cytotoxic strategies in cancer treatment.

*Corresponding author. E-mail, peter.vandenabeele{at}dmbr.ugent.be

Citation: P. Vandenabeele, T. Vanden Berghe, N. Festjens, Caspase Inhibitors Promote Alternative Cell Death Pathways. Sci. STKE 2006, pe44 (2006).

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