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Sci. STKE, 24 October 2006
Vol. 2006, Issue 358, p. pe44
Caspase Inhibitors Promote Alternative Cell Death Pathways
Tom Vanden Berghe, and
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.
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-fmkmediated sensitization to necrotic cell death involves the inhibition of caspase-8mediated 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.
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