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.
Bagnoli
Marina
M
Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan, Italy. marina.bagnoli@istitutotumori.mi.it
Canevari
Silvana
S
Mezzanzanica
Delia
D
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein