c-FLIP, a master anti-apoptotic regulator.

Abstract

Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a master anti-apoptotic regulator and resistance factor that suppresses tumor necrosis factor-α (TNF-α), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, as well as apoptosis triggered by chemotherapy agents 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 and TRAIL receptor 5 (DR5) in a ligand-dependent and -independent fashion and forms an apoptosis inhibitory complex (AIC). This interaction in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIP(L) and c-FLIP(S) are also known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective and pro-survival signaling proteins including Akt, ERK, and NF-kB. Upregulation of c-FLIP has been found in various tumor types, and its silencing 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 much effort is focused on developing other c-FLIP-targeted cancer therapies. This review focuses on (1) the anti-apoptotic role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and chemotherapy drug resistance, (2) the molecular mechanisms and factors that regulate c-FLIP expression, and (3) modulation of c-FLIP expression and function to eliminate cancer cells or increase the efficacy of anticancer agents. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".

• Authors: A R Safa
• Journal: Experimental oncology (Exp Oncol) Vol. 34 Issue 3 Pg. 176-84 (Oct 2012) ISSN: 1812-9269 [Print] Ukraine
• PMID: 23070002 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Review)

Chemical References

• Antineoplastic Agents
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• FADD protein, human
• Fas-Associated Death Domain Protein
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Caspase 8

Topics

• Antineoplastic Agents (therapeutic use)
• Apoptosis
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Caspase 8 (metabolism)
• Drug Resistance, Neoplasm (genetics)
• Fas-Associated Death Domain Protein (metabolism)
• Humans
• Neoplasms (drug therapy, metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Signal Transduction