Regulation of extrinsic apoptotic signaling by c-FLIP: Towards targeting cancer networks
c-FLIP is a master regulator of death receptor-induced apoptosis.
The molecular architecture of the death-inducing signaling complex (DISC) is strongly regulated by c-FLIP proteins.
Recently, several structural and mechanistic models of this control have been proposed.
c-FLIP can act in both a pro- and antiapoptotic manner in cancer cells.
c-FLIP is a promising target in cancer.
Targeting c-FLIP has a great potential to sensitize cancer cells towards apoptosis induction.
The extrinsic pathway is mediated by death receptors (DRs), including CD95 (APO-1/Fas) or TRAILR-1/2. Defects in apoptosis regulation lead to cancer and other malignancies. The master regulator of the DR networks is the cellular FLICE inhibitory protein (c-FLIP). In addition to its key role in apoptosis, c-FLIP may exert other cellular functions, including control of necroptosis, pyroptosis, nuclear factor κB (NF-κB) activation, and tumorigenesis. To gain further insight into the molecular mechanisms of c-FLIP action in cancer networks, we focus on the structure, isoforms, interactions, and post-translational modifications of c-FLIP. We also discuss various avenues to target c-FLIP in cancer cells for therapeutic benefit.