Cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory
protein (c-FLIP) is a major resistance factor and critical anti-apoptotic regulator that inhibits
tumor necrosis factor-alpha (
TNF-alpha), Fas-L, and
TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis as well as
chemotherapy-triggered apoptosis in malignant cells. c-FLIP is expressed as long (c-
FLIP(L)), short (c-
FLIP(S)), and c-FLIP(R) splice variants in human cells. c-FLIP binds to FADD and/or
caspase-8 or -10 in a
ligand-dependent and-independent fashion, which in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the
caspase cascade. Moreover, c-
FLIP(L) and c-
FLIP(S) are known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective signaling molecules. Upregulation of c-FLIP has been found in various
tumor types, and its downregulation has been shown to restore apoptosis triggered by
cytokines and various chemotherapeutic agents. Hence, c-FLIP is an important target for
cancer therapy. For example, small interfering RNAs (siRNAs) that specifically knockdown the expression of c-
FLIP(L) in diverse human
cancer cell lines augmented TRAIL-induced DISC recruitment and increased the efficacy of chemotherapeutic agents, thereby enhancing effector
caspase stimulation and apoptosis. Moreover, small molecules causing degradation of c-FLIP as well as decreasing
mRNA and
protein levels of c-
FLIP(L) and c-
FLIP(S) splice variants have been found, and efforts are underway to develop other c-FLIP-targeted
cancer therapies. This review focuses on (1) the functional role of c-FLIP splice variants in preventing apoptosis and inducing
cytokine and drug resistance; (2) the molecular mechanisms that regulate c-FLIP expression; and (3) strategies to inhibit c-FLIP expression and function.