Caspase inhibitors promote alternative cell death pathways.
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.
Vandenabeele
Peter
P
Molecular Signalling and Cell Death Unit, Department for Molecular Biomedical Research, Flanders Interuniversity Institute of Biotechnology (VIB), Ghent, Belgium. peter.vandenabeele@dmbr.ugent.be
Vanden Berghe
Tom
T
Festjens
Nele
N
D033741:Adenine Nucleotide Translocator 1 / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006801:Humans; D009336:Necrosis; D009369:Neoplasms / Q000473:pathology; D028861:Nuclear Pore Complex Proteins / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D016601:RNA-Binding Proteins / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
C119724:AGFG1 protein, human; D033741:Adenine Nucleotide Translocator 1; D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D000081406:Peptidyl-Prolyl Isomerase F; D015853:Cysteine Proteinase Inhibitors; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D021983:Cyclophilins