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Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy
Department of Pharmacology and Toxicology, Indiana University School of Medicine, 980 W. Walnut Street, R3-C524, Indianapolis, IN 46202, USA
Indiana University Simon Cancer Center, Indiana University School of Medicine, 980 W. Walnut Street, R3-C524, Indianapolis, IN 46202, USA
Herman B. Wells Center for Pediatric Research, 980 W. Walnut Street, R3-C524, Indianapolis, IN 46202, USA
* Author to whom correspondence should be addressed.
Received: 26 February 2011; in revised form: 15 March 2011 / Accepted: 16 March 2011 / Published: 29 March 2011
Abstract: 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-FLIPL), short (c-FLIPS), and c-FLIPR 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-FLIPL and c-FLIPS 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-FLIPL 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-FLIPL and c-FLIPS 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.
Keywords: c-FLIP; apoptosis; death receptors; cancer; chemotherapy
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MDPI and ACS Style
Safa, A.R.; Pollok, K.E. Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy. Cancers 2011, 3, 1639-1671.
Safa AR, Pollok KE. Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy. Cancers. 2011; 3(2):1639-1671.
Safa, Ahmad R.; Pollok, Karen E. 2011. "Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy." Cancers 3, no. 2: 1639-1671.