alexa Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy
ISSN: 2157-2518

Journal of Carcinogenesis & Mutagenesis
Open Access

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Review Article

Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy

Ahmad R Safa1,2*

1Department of Pharmacology &Toxicology, Indiana University School of Medicine, IN 46202, USA

2Indiana University Simon Cancer Center, Indiana University School of Medicine, IN 46202, USA

*Corresponding Author:
Ahmad R. Safa
Department of Pharmacology & Toxicology
Indiana University School of Medicine, IN 46202, USA
Tel: 317-278-4952
Fax: +1-317-274-8046
E-mail: [email protected]

Received date: April 20, 2013; Accepted date: June 06, 2013; Published date: June 20, 2013

Citation: Safa AR (2013) Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy. J Carcinogene Mutagene S6:003. doi: 10.4172/2157-2518.S6-003

Copyright: © 2013 Safa AR. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 

Abstract

Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a major antiapoptotic protein and an important cytokine and chemotherapy resistance factor that suppresses cytokine- and chemotherapyinduced apoptosis. 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 and TRAIL receptor 5 (DR5). This interaction in turn prevents Death-Inducing Signaling Complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIPL and c-FLIPS 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-κB. In addition to its role in apoptosis, c-FLIP is involved in programmed necroptosis (necrosis) and autophagy. Necroptosis is regulated by the Ripoptosome, which is a signaling intracellular cell death platform complex. The Ripoptosome contains receptor-interacting protein-1/Receptor-Interacting Protein-3 (RIP1), caspase-8, caspase-10, FADD, and c-FLIP isoforms involved in switching apoptotic and necroptotic cell death. c-FLIP regulates the Ripoptosome; in addition to its role in apoptosis, it is therefore also involved in necrosis. c-FLIPL attenuates autophagy by direct acting on the autophagy machinery by competing with Atg3 binding to LC3, thereby decreasing LC3 processing and inhibiting autophagosome formation. 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. This review focuses on (1) the anti-apoptotic role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and chemotherapy drug resistance, as well as its roles in necrosis and autophagy, and (2) modulation of c-FLIP expression as a means to enhance apoptosis and modulate necrosis and autophagy in cancer cells.

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