Abstract
A better understanding of the mechanisms through which anticancer drugs exert their effects is essential to improve combination therapies. While studying how genotoxic stress kills cancer cells, we discovered a large ∼2MDa cell death-inducing platform, referred to as "Ripoptosome." It contains the core components RIP1, FADD, and caspase-8, and assembles in response to genotoxic stress-induced depletion of XIAP, cIAP1 and cIAP2. Importantly, it forms independently of TNF, CD95L/FASL, TRAIL, death-receptors, and mitochondrial pathways. It also forms upon Smac-mimetic (SM) treatment without involvement of autocrine TNF. Ripoptosome assembly requires RIP1's kinase activity and can stimulate caspase-8-mediated apoptosis as well as caspase-independent necrosis. It is negatively regulated by FLIP, cIAP1, cIAP2, and XIAP. Mechanistically, IAPs target components of this complex for ubiquitylation and inactivation. Moreover, we find that etoposide-stimulated Ripoptosome formation converts proinflammatory cytokines into prodeath signals. Together, our observations shed new light on fundamental mechanisms by which chemotherapeutics may kill cancer cells.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology*
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
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CASP8 and FADD-Like Apoptosis Regulating Protein / physiology
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Caspase 8 / chemistry
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Caspase 8 / metabolism
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Caspase 8 / physiology*
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Cell Line, Tumor
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DNA Damage*
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Enzyme Activation
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Etoposide / pharmacology
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Fas-Associated Death Domain Protein / chemistry
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Fas-Associated Death Domain Protein / metabolism
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Fas-Associated Death Domain Protein / physiology*
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Humans
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Inhibitor of Apoptosis Proteins / genetics*
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Inhibitor of Apoptosis Proteins / physiology
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Ligands
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Mitochondria / metabolism
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Nuclear Pore Complex Proteins / chemistry
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Nuclear Pore Complex Proteins / metabolism
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Nuclear Pore Complex Proteins / physiology*
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RNA-Binding Proteins / chemistry
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RNA-Binding Proteins / metabolism
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RNA-Binding Proteins / physiology*
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Signal Transduction
Substances
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AGFG1 protein, human
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Antineoplastic Agents
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CASP8 and FADD-Like Apoptosis Regulating Protein
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FADD protein, human
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Fas-Associated Death Domain Protein
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Inhibitor of Apoptosis Proteins
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Ligands
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Nuclear Pore Complex Proteins
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RNA-Binding Proteins
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Etoposide
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CASP8 protein, human
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Caspase 8