Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy

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