Signalling networks in focus
Cellular FLICE-inhibitory protein (c-FLIP) signalling: A key regulator of receptor-mediated apoptosis in physiologic context and in cancer

https://doi.org/10.1016/j.biocel.2009.11.015Get rights and content

Abstract

Cellular FLICE-inhibitory protein (c-FLIP) is a catalytically inactive procaspase-8/10 homologue that associates with the signalling complex downstream of death-receptors negatively interfering with apoptotic signalling. Three c-FLIP splice variants have been identified: c-FLIPL, c-FLIPS and c-FLIPR, with all three functioning as apoptosis inhibitors involved in modulation of caspase-8/10 activity in both physiologic and pathologic contexts. Furthermore, a cell-type specific pro-apoptotic role, depending on caspase-8 to c-FLIPL ratio, has also been described for the long isoform. The present review summarizes recent findings concerning c-FLIP proteins’ function and regulation, with a main focus on the c-FLIPL deregulated expression in cancer. The role of c-FLIPL as anti-apoptotic pro-survival factor in tumors and the potential utility of this molecule as a possible alternative therapeutic target are discussed.

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.

References (29)

  • T.W. Day et al.

    RNA interference in cancer: targeting the anti-apoptotic protein c-FLIP for drug discovery

    Mini Rev Med Chem

    (2009)
  • P. Geserick et al.

    Suppression of cFLIP is sufficient to sensitize human melanoma cells to TRAIL- and CD95L-mediated apoptosis

    Oncogene

    (2008)
  • A. Golks et al.

    The c-FLIP-NH2 terminus (p22-FLIP) induces NF-kappaB activation

    J Exp Med

    (2006)
  • M. Irmler et al.

    Inhibition of death receptor signals by cellular FLIP

    Nature

    (1997)
  • Cited by (117)

    • An engineered construct of cFLIP provides insight into DED1 structure and interactions

      2022, Structure
      Citation Excerpt :

      Approximately 20% of the aforementioned PPIs involve just the seven members of the DED subfamily (FADD, procaspase-8, procaspase-10, cFLIP, DEDD, DEDD2, and PEA-15) (Kwon et al., 2012). cFLIP has been shown to associate through homotypic DED/DED interactions with both the adaptor protein FADD and with procaspase-8, as key players in the assembly of the death-inducing signaling complex (DISC) and the regulation of extrinsic apoptosis (Bagnoli et al., 2010; Fu et al., 2016; Hengartner, 2000; Hillert et al., 2020; Hughes et al., 2016; Hwang et al., 2013, 2014; Irmler et al., 1997; Kaminskyy et al., 2013; Majkut et al., 2014; Öztürk et al., 2012; Plati et al., 2011; Safa, 2012; Schleich et al., 2016; Ueffing et al., 2008; Wilson et al., 2007; Yang, 2008). Additionally, the importance of these proteins and their interactions has been shown for embryonic development, T cell stimulation, cell cycle progression and proliferation, necroptosis inhibition in adaptive immune responses, and activation of the NLRP3 inflammasome (Gilot et al., 2005; Gurung et al., 2014; Kennedy et al., 1999; Misra et al., 2007; Mogi and Togari, 2003; Varfolomeev et al., 1998; Walsh et al., 1998; Yeh et al., 1998, 2000).

    • The TRAIL to cancer therapy: Hindrances and potential solutions

      2019, Critical Reviews in Oncology/Hematology
    View all citing articles on Scopus
    View full text