Cellular FLICE-inhibitory protein (c-FLIP) signalling: a key regulator of receptor-mediated apoptosis in physiologic context and in cancer.

Cellular FLICE-inhibitory protein (c-FLIP) is a catalytically inactive procaspase-8/10 homologue that associates with the signalling complex downstream of death-receptors negatively interfering with apoptotic signalling. Three c-FLIP splice variants have been identified: c-FLIP(L), c-FLIP(S) and c-FLIP(R), with all three functioning as apoptosis inhibitors involved in modulation of caspase-8/10 activity in both physiologic and pathologic contexts. Furthermore, a cell-type specific pro-apoptotic role, depending on caspase-8 to c-FLIP(L) ratio, has also been described for the long isoform. The present review summarizes recent findings concerning c-FLIP proteins' function and regulation, with a main focus on the c-FLIP(L) deregulated expression in cancer. The role of c-FLIP(L) as anti-apoptotic pro-survival factor in tumors and the potential utility of this molecule as a possible alternative therapeutic target are discussed.