Abstract
CD95 apoptosis resistance of tumor cells is often acquired through mutations in the death domain (DD) of one of the CD95 alleles. Furthermore, Type I cancer cells are resistant to induction of apoptosis by soluble CD95 ligand (CD95L), which does not induce efficient formation of the death-inducing signaling complex (DISC). Here, we report that tumor cells expressing a CD95 allele that lacks a functional DD, splenocytes from heterozygous lpr(cg) mice, which express one mutated CD95 allele, and Type I tumor cells stimulated with soluble CD95L can all die through CD95 when protein synthesis or nuclear factor kappa B is inhibited. This noncanonical form of CD95-mediated apoptosis is dependent on the enzymatic activity of procaspase-8 but does not involve fully processed active caspase-8 subunits. Our data suggest that it is possible to overcome the CD95 apoptosis resistance of many tumor cells that do not efficiently form a DISC through noncanonical activation of the caspase-8 proenzyme.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alleles
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology*
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Caspase 8
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Caspase Inhibitors
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Caspases / metabolism*
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Cell Line, Tumor
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Cell Survival / drug effects
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Cycloheximide / pharmacology
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Cysteine Proteinase Inhibitors / pharmacology
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Dactinomycin / pharmacology
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Death Domain Receptor Signaling Adaptor Proteins
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Drug Resistance, Neoplasm
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Enzyme Activation
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Fas Ligand Protein
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Humans
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Membrane Glycoproteins / pharmacology
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Mice
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Mice, Inbred C3H
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mutation
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NF-kappa B / antagonists & inhibitors
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Oligopeptides / pharmacology
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Receptors, Tumor Necrosis Factor / metabolism
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fas Receptor / genetics
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fas Receptor / physiology*
Substances
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Amino Acid Chloromethyl Ketones
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Antineoplastic Agents
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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Death Domain Receptor Signaling Adaptor Proteins
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FASLG protein, human
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Fas Ligand Protein
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Fasl protein, mouse
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Membrane Glycoproteins
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NF-kappa B
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Oligopeptides
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Receptors, Tumor Necrosis Factor
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benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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fas Receptor
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Dactinomycin
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Cycloheximide
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CASP8 protein, human
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Casp8 protein, mouse
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Caspase 8
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Caspases