Selective inhibition of FLICE-like inhibitory protein expression with small interfering RNA oligonucleotides is sufficient to sensitize @entity5 cells for XXXX -induced apoptosis.

@entity1 @entity1182 @entity39 @entity5 @entity2205 @entity3048 @entity8186 @entity3049
BACKGROUND: Most @entity5 express death receptors and their activation represents a potential selective approach in @entity5 treatment. The most promising candidate for @entity5 selective death receptor-activation is @entity5 @entity39 factor-related apoptosis-inducing ligand ( @entity2205 )/ @entity2205 , which activates the death receptors @entity3048 and @entity3049 , and induces apoptosis preferentially in @entity5 cells but not in normal tissues. However, many @entity5 cells are not or only moderately sensitive towards @entity2205 and require cotreatment with irradiation or chemotherapy to yield a therapeutically reasonable apoptotic response. Because chemotherapy can have a broad range of unwanted side effects, more specific means for sensitizing @entity5 cells for @entity2205 are desirable. The expression of the @entity1182 ( @entity1182 ) is regarded as a major cause of @entity2205 resistance. We therefore analyzed the usefulness of targeting @entity1182 to sensitize @entity5 cells for @entity2205 -induced apoptosis. MATERIALS AND METHODS: To selectively interfere with expression of @entity1182 short double-stranded RNA oligonucleotides (small interfering RNAs [siRNAs]) were introduced in the @entity1 cell lines SV80 and KB by electroporation. Effects of siRNA on @entity1182 expression were analyzed by Western blotting and RNase protection assay and correlated with @entity2205 sensitivity upon stimulation with recombinant soluble @entity2205 and @entity3048 - and @entity3049 -specific agonistic antibodies. RESULTS: @entity1182 expression can be inhibited by RNA interference using siRNAs, evident from reduced levels of @entity1182 -mRNA and @entity1182 protein. Inhibition of @entity1182 expression sensitizes cells for apoptosis induction by @entity2205 and other death ligands. In accordance with the presumed function of @entity1182 as an inhibitor of death receptor-induced @entity8186 activation, down-regulation of @entity1182 by siRNAs enhanced @entity2205 -induced @entity8186 activation. CONCLUSION: Inhibition of @entity1182 expression was sufficient to sensitize @entity5 cells for @entity2205 -induced apoptosis. The combination of @entity2205 and @entity1182 -targeting siRNA could therefore be a useful strategy to attack @entity5 cells, which are resistant to @entity2205 alone.
