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Tumor Biology |
University Children’s Hospital, D-89075 Ulm, Germany
Protein or RNA synthesis inhibitors are known to sensitize some
resistant cells for death receptor-induced apoptosis. However, the
molecular mechanism(s) involved in sensitization have not yet been
defined exactly. Here, we report that metabolic inhibitors such as
cycloheximide (CHX) or actinomycin D (ActD) sensitize for CD95-induced
apoptosis by strongly down-regulating FLIP and RIP expression.
Metabolic labeling studies revealed that CHX or ActD inhibited protein
or RNA synthesis at concentrations required for sensitization. In
contrast to Fas-associated death domain (FADD) or caspase-8, FADD-like
interleukin 1-converting enzyme-inhibitory protein (FLIP) and RIP
protein levels rapidly decreased upon treatment with CHX or ActD,
indicating that both molecules have a high turnover rate. Selective
down-regulation of FLIP expression by FLIP antisense oligonucleotides
sensitized for CD95-induced apoptosis. Reduction of FLIP levels
resulted in undetectable amounts of FLIP at the CD95 death-inducing
signaling complex (DISC) upon CD95 stimulation, thereby enhancing the
recruitment of caspase-8 to the DISC and caspase-8 activation. CHX- or
ActD-mediated sensitization to CD95-induced apoptosis was predominantly
found in type I cells in which FADD and caspase-8 are recruited to CD95
upon stimulation but not in type II cells in which no DISC formation is
detected. Pretreatment with CHX or ActD sensitized for subsequent CD95
stimulation compared with cells without pretreatment. CHX or ActD also
reduced XIAP expression and similarly sensitized for tumor necrosis
factor-related apoptosis-inducing ligand- or tumor necrosis
factor-
-induced apoptosis. Because blockade of death receptor
triggering by FLIP overexpression has recently been implicated in
tumorigenesis and treatment resistance in vivo,
strategies to inhibit FLIP expression, e.g., by
metabolic inhibitors, may prove to be a useful complementary tool for
the treatment of cancer.
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