Dual roles of FLIP in controlling caspase-8 and their implications on cell death and survival

Cellular FLIP (cFLIP; cellular FLICE inhibitory protein) is a key regulator of caspase-8 activity, and its viral homolog (vFLIP) is found in various viruses. cFLIP inhibits the caspase-8 activation in death-inducing signaling complex (DISC) when its expression level is high as in cancer cells. In contrast, cFLIP can also activate the caspase-8 in its lower expression level and in lymphocyte in particular which results in the activation of NF-κB transcription factor. Recent biochemical studies on DISC has proposed that DED proteins in DISC, that are FADD, procaspase-8 & cFLIP, utilize two hydrophobic faces of their DEDs for establishing DED-DED network for DISC assembly. Regarding the NF-κB activation, the crystal structure of K13-vFLIP showed that two grooves in the N-terminal DED in FLIP are the sites where dimeric IKKγ binds. FLIP is associated with various cancers seemingly through the dual functions of inhibiting apoptosis and promoting proliferation, so it would an attractive anti-cancer therapeutic target at either mRNA or protein level.