The International Journal of Biochemistry & Cell Biology
Signalling networks in focusCellular FLICE-inhibitory protein (c-FLIP) signalling: A key regulator of receptor-mediated apoptosis in physiologic context and in cancer
Introduction
Apoptosis or programmed cell death is essential for normal development and tissue homeostasis. By activating the caspase family proteins, apoptosis triggers the activation of a proteolytic cascade that drives subsequent biochemical events leading to cell death. Two major interplaying apoptotic signalling pathways have been identified: the intrinsic mitochondrial-dependent pathway, sensing intracellular signals such as DNA damage, and the extrinsic receptor-dependent pathway. Triggering of death-receptors [CD95-Fas, Tumor Necrosis Factor-R (TNFR) and TNF-Related Apoptosis-Inducing Ligand-R1/R2 (TRAIL-R1/R2)] by cognate ligands (FasL, TRAIL, TNFα) induces, by means of the receptors’ intracellular Dead Domain (DD), the recruitment of death adaptor proteins like Fas-Associated Death-Domain (FADD) or TRAIL Receptor-Associated Death-Domain (TRADD). Death-receptors also possess a Death Effector Domain (DED) that is necessary to recruit, through homophilic interaction, initiator procaspases-8/10 to form the Death Inducing Signalling Complex (DISC). DISC formation, favouring procaspase dimerization, also enables their trans-proteolytic cleavage and activates a proteolytic cascade ending with activation of executioner caspase-3/7 (Johnstone et al., 2002).
Cellular FLICE-inhibitory protein (c-FLIP) is a catalytically inactive caspase-8/10 homologue that interferes with efficient DISC formation in the extrinsic pathway directly at the receptor level (Irmler et al., 1997, Scaffidi et al., 1999). c-FLIP was described as a subtle regulator with pro- and anti-apoptotic effects in development and in normal adult tissues. Dysregulation of c-FLIP expression was observed in autoimmune diseases and several cancer types (reviewed in Safa et al., 2008). This review will mainly focus on the role of c-FLIP as anti-apoptotic, pro-survival factor in cancer and on the evaluation of this molecule as a possible therapeutic target.
Section snippets
Function
So far, 11 c-FLIP splicing variants have been identified and three of them were detected as cellular proteins: the 26 kDa short form c-FLIPS, the 24 kDa form c-FLIPR and the 55 kDa long form c-FLIPL. Their structure is similar, with two DED motifs at their amino-terminus. In the shorter forms, the tandem DED motif is followed, at the carboxy-terminus, by a variable length stretch of aminoacids that is crucial for c-FLIP ubiquitylation and degradation. c-FLIPL has a carboxy-terminus longer than
TRAIL-R and CD95/FAS signalling
Death-receptors belonging to the tumor necrosis factor receptor family play an important role in apoptosis. Elevated c-FLIP expression is a critical factor in causing both CD95 and TRAIL resistance in different cancer cell types and it may interfere with death-receptor signalling potentiating the survival pathway (Newsom-Davis et al., 2009). In most cases, resistance occurs at the level of DISC where an increase in c-FLIP expression prevents procaspase-8 recruitment and activation (Mezzanzanica
c-FLIP in pathologic context and therapeutic implications
Tumor cells can evade apoptosis through several mechanisms that affect both intrinsic and extrinsic apoptotic pathways, and resistance to chemotherapeutic treatment is frequently related to failure of programmed cell death.
Increased c-FLIP expression has been observed in several human malignancies, such as ovarian, colon, breast and prostate cancer and glioblastoma, and it was found to be involved in resistance to both CD95/Fas- and TRAIL receptor-induced apoptosis in most of them. Resistance
Acknowledgements
We thank Mrs G. Barp for manuscript preparation. Work is funded by grants from: Associazione Italiana Ricerca Cancro (AIRC); Programma Straordinario Oncologia 2006 and Programma Tumori Femminili 2008 Ministry of Health, Italy.
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