Cellular FLICE-like inhibitory protein (C-FLIP): a novel target for cancer therapy.
Cellular FLICE-like inhibitory protein (c-FLIP) has been identified as a protease-dead, procaspase-8-like regulator of death ligand-induced apoptosis, based on observations that c-FLIP impedes tumor necrosis factor-alpha (TNF-alpha), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by binding to FADD and/or caspase-8 or -10 in a ligand-dependent fashion, which in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIP is a family of alternatively spliced variants, and primarily exists as long (c-FLIP(L)) and short (c-FLIP(S)) splice variants in human cells. Although c-FLIP has apoptogenic activity in some cell contexts, which is currently attributed to heterodimerization with caspase-8 at the DISC, accumulating evidence indicates an anti-apoptotic role for c-FLIP in various types of human cancers. For example, small interfering RNAs (siRNAs) that specifically knocked down expression of c-FLIP(L) in diverse human cancer cell lines, e.g., lung and cervical cancer cells, augmented TRAIL-induced DISC recruitment, and thereby enhanced effector caspase stimulation and apoptosis. Therefore, the outlook for the therapeutic index of c-FLIP-targeted drugs appears excellent, not only from the efficacy observed in experimental models of cancer therapy, but also because the current understanding of dual c-FLIP action in normal tissues supports the notion that c-FLIP-targeted cancer therapy will be well tolerated. Interestingly, Taxol, TRAIL, as well as several classes of small molecules induce c-FLIP downregulation in neoplastic cells. Efforts are underway to develop small-molecule drugs that induce c-FLIP downregulation and other c-FLIP-targeted cancer therapies. In this review, we assess the outlook for improving cancer therapy through c-FLIP-targeted therapeutics.
Safa
Ahmad R
AR
Department of Pharmacology and Toxicology, Indiana University Cancer Center, Indiana University School of Medicine, 1044 W. Walnut St., Indianapolis, IN 46202, USA. asafa@iupui.edu
Day
Travis W
TW
Wu
Ching-Huang
CH
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*
D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human