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FLIP

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Cancer Therapeutic Targets

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Abstract

FLIP (FLICE-Inhibitory Protein), also known as c-FLIP, Casper, Cash, CLARP, I-Flice, Flame-1, MRIT or usurpin is a cytosolic protein that can be expressed as three isoforms. cFLIPs are considered as the most potent inhibitors of caspase-8, an initiator caspase required for apoptosis triggering by the extrinsic pathway. Owing to their structural homology with caspase-8, c-FLIPs can be recruited to macromolecular complexes arising from the stimulation of membrane-bound receptors such as members of the TNF or Toll-like receptor superfamilly. Since they are often overexpressed in cancer cells, cFLIPs are considered as interesting targets for cancer therapy. Recent advances in our understanding of cFLIPs expression or stability through post-translational modifications and/or signaling pathways are discussed here to provide ground for future targeting in oncology

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References

  • Aragane Y, et al. Ultraviolet light induces apoptosis via direct activation of CD95 (Fas/APO-1) independently of its ligand CD95L. J Cell Biol. 1998;140:171–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bucur O, et al. Poor antibody validation is a challenge in biomedical research: a case study for detection of c-FLIP. Apoptosis. 2013;18:1154–62.

    Article  CAS  PubMed  Google Scholar 

  • Chang L, et al. The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell. 2006;124:601–13.

    Article  CAS  PubMed  Google Scholar 

  • Chanvorachote P, et al. Nitric oxide negatively regulates Fas CD95-induced apoptosis through inhibition of ubiquitin-proteasome-mediated degradation of FLICE inhibitory protein. J Biol Chem. 2005;280:42044–50.

    Article  CAS  PubMed  Google Scholar 

  • Dickens LS, et al. A death effector domain chain DISC model reveals a crucial role for caspase-8 chain assembly in mediating apoptotic cell death. Mol Cell. 2012;47:291–305.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Djerbi M, et al. The inhibitor of death receptor signaling, FLICE-inhibitory protein defines a new class of tumor progression factors. J Exp Med. 1999;190:1025–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dong HP, et al. Flow cytometric measurement of cellular FLICE-inhibitory protein (c-FLIP) in ovarian carcinoma effusions. Cytopathology. 2011;22:373–82.

    Article  CAS  PubMed  Google Scholar 

  • Estornes Y, et al. dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8. Cell Death Differ. 2012;19:1482–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Feoktistova M, et al. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell. 2011;43:449–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Galligan L, et al. Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP. Mol Cancer Ther. 2005;4:2026–36.

    Article  CAS  PubMed  Google Scholar 

  • Goltsev YV, et al. CASH, a novel caspase homologue with death effector domains. J Biol Chem. 1997;272:19641–4.

    Article  CAS  PubMed  Google Scholar 

  • Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ. Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol. 1998;161:2833–40.

    CAS  PubMed  Google Scholar 

  • Han DK, et al. MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death. Proc Natl Acad Sci U S A. 1997;94:11333–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hu S, Vincenz C, Ni J, Gentz R, Dixit VM. I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD-95-induced apoptosis. J Biol Chem. 1997;272:17255–7.

    Article  CAS  PubMed  Google Scholar 

  • Inohara N, Koseki T, Hu Y, Chen S, Nunez G. CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis. Proc Natl Acad Sci U S A. 1997;94:10717–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Iordanov MS, et al. Recruitment of TRADD, FADD, and caspase 8 to double-stranded RNA-triggered death inducing signaling complexes (dsRNA-DISCs). Apoptosis. 2005;10:167–76.

    Article  CAS  PubMed  Google Scholar 

  • Irmler M, et al. Inhibition of death receptor signals by cellular FLIP. Nature. 1997;388:190–5.

    Article  CAS  PubMed  Google Scholar 

  • Kaunisto A, et al. PKC-mediated phosphorylation regulates c-FLIP ubiquitylation and stability. Cell Death Differ. 2009;16:1215–26.

    Article  CAS  PubMed  Google Scholar 

  • Kerr E, et al. Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. Cell Death Differ. 2012;19:1317–27.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Korkolopoulou P, et al. c-FLIP expression in bladder urothelial carcinomas: its role in resistance to Fas-mediated apoptosis and clinicopathologic correlations. Urology. 2004;63:1198–204.

    Article  PubMed  Google Scholar 

  • Kundu M, et al. A TNF- and c-Cbl-dependent FLIP(S)-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis. Nat Immunol. 2009;10:918–26.

    Article  CAS  PubMed  Google Scholar 

  • Lawlor KE, et al. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat Commun. 2015;6:6282.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Logan AE, et al. In vitro and in vivo characterisation of a novel c-FLIP-targeted antisense phosphorothioate oligonucleotide. Apoptosis. 2010;15:1435–43.

    Article  CAS  PubMed  Google Scholar 

  • Longley DB, et al. c-FLIP inhibits chemotherapy-induced colorectal cancer cell death. Oncogene. 2006;25:838–48.

    Article  CAS  PubMed  Google Scholar 

  • Lu M, et al. Cell death. Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science. 2014;345:98–101.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Majkut J, et al. Differential affinity of FLIP and procaspase 8 for FADD’s DED binding surfaces regulates DISC assembly. Nat Commun. 2014;5:3350.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McLornan DP, et al. Prognostic significance of TRAIL signaling molecules in stage II and III colorectal cancer. Clin Cancer Res. 2010;16:3442–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McLornan D, et al. Prognostic and therapeutic relevance of c-FLIP in acute myeloid leukaemia. Br J Haematol. 2013;160:188–98.

    Article  CAS  PubMed  Google Scholar 

  • Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114:181–90.

    Article  CAS  PubMed  Google Scholar 

  • Micheau O, Solary E, Hammann A, Dimanche-Boitrel MT. Fas ligand-independent, FADD-mediated activation of the Fas death pathway by anticancer drugs. J Biol Chem. 1999;274:7987–92.

    Article  CAS  PubMed  Google Scholar 

  • Micheau O, et al. The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. J Biol Chem. 2002;277:45162–71.

    Article  CAS  PubMed  Google Scholar 

  • Micheau O, Shirley S, Dufour F. Death receptors as targets in cancer. Br J Pharmacol. 2013;169:1723–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mori T, et al. Regulation of the resistance to TRAIL-induced apoptosis as a new strategy for pancreatic cancer. Surgery. 2005;138:71–7.

    Article  PubMed  Google Scholar 

  • Morizot A, et al. Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level. Cell Death Differ. 2011;18:700–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Morlé A, Garrido C, Micheau O. Hyperthermia restores apoptosis induced by death receptors through aggregation-induced c-FLIP cytosolic depletion. Cell Death Dis. 2015;6:e1633.

    Article  PubMed Central  PubMed  Google Scholar 

  • Panner A, et al. A novel PTEN-dependent link to ubiquitination controls FLIPS stability and TRAIL sensitivity in glioblastoma multiforme. Cancer Res. 2009;69:7911–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rao-Bindal K, Rao CK, Yu L, Kleinerman ES. Expression of c-FLIP in pulmonary metastases in osteosarcoma patients and human xenografts. Pediatr Blood Cancer. 2013;60:575–9.

    Article  PubMed  Google Scholar 

  • Rasper DM, et al. Cell death attenuation by ‘Usurpin’, a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex. Cell Death Differ. 1998;5:271–88.

    Article  CAS  PubMed  Google Scholar 

  • Ricci MS, et al. Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity. Mol Cell Biol. 2004;24:8541–55.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Riley JS, et al. Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer. Cell Death Dis. 2013;4:e951.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rogers KM, et al. Cellular FLICE-inhibitory protein regulates chemotherapy-induced apoptosis in breast cancer cells. Mol Cancer Ther. 2007;6:1544–51.

    Article  CAS  PubMed  Google Scholar 

  • Schmid SJ, et al. Absence of FLICE-inhibitory protein is a novel independent prognostic marker for very short survival in pancreatic ductal adenocarcinoma. Pancreas. 2013;42:1114–9.

    Article  CAS  PubMed  Google Scholar 

  • Sheikh MS, Antinore MJ, Huang Y, Fornace Jr AJ. Ultraviolet-irradiation-induced apoptosis is mediated via ligand independent activation of tumor necrosis factor receptor 1. Oncogene. 1998;17:2555–63.

    Article  CAS  PubMed  Google Scholar 

  • Shi B, Tran T, Sobkoviak R, Pope RM. Activation-induced degradation of FLIP(L) is mediated via the phosphatidylinositol 3-kinase/Akt signaling pathway in macrophages. J Biol Chem. 2009;284:14513–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shirley S, Micheau O. Targeting c-FLIP in cancer. Cancer Lett. 2013;332:141–50.

    Article  CAS  PubMed  Google Scholar 

  • Shu HB, Halpin DR, Goeddel DV. Casper is a FADD- and caspase-related inducer of apoptosis. Immunity. 1997;6:751–63.

    Article  CAS  PubMed  Google Scholar 

  • Song X, et al. Hyperthermia enhances mapatumumab-induced apoptotic death through ubiquitin-mediated degradation of cellular FLIP(long) in human colon cancer cells. Cell Death Dis. 2013;4:e577.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Srinivasula SM, et al. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis. J Biol Chem. 1997;272:18542–5.

    Article  CAS  PubMed  Google Scholar 

  • Su L, et al. Death receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells. Eur J Cancer. 2011;47:2471–8.

    Article  CAS  PubMed  Google Scholar 

  • Thome M, et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature. 1997;386:517–21.

    Article  CAS  PubMed  Google Scholar 

  • Travert M, et al. CD40 ligand protects from TRAIL-induced apoptosis in follicular lymphomas through NF-kappaB activation and up-regulation of c-FLIP and Bcl-xL. J Immunol. 2008;181:1001–11.

    Article  CAS  PubMed  Google Scholar 

  • Ullenhag GJ, et al. Overexpression of FLIPL is an independent marker of poor prognosis in colorectal cancer patients. Clin Cancer Res. 2007;13:5070–5.

    Article  CAS  PubMed  Google Scholar 

  • Valente G, et al. cFLIP expression correlates with tumour progression and patient outcome in non-Hodgkin lymphomas of low grade of malignancy. Br J Haematol. 2006;132:560–70.

    Article  CAS  PubMed  Google Scholar 

  • Valnet-Rabier MB, et al. c-Flip protein expression in Burkitt’s lymphomas is associated with a poor clinical outcome. Br J Haematol. 2005;128:767–73.

    Article  CAS  PubMed  Google Scholar 

  • Wang W, et al. The relationship between c-FLIP expression and human papillomavirus E2 gene disruption in cervical carcinogenesis. Gynecol Oncol. 2007;105:571–7.

    Article  CAS  PubMed  Google Scholar 

  • Weng D, et al. Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death. Proc Natl Acad Sci U S A. 2014;111:7391–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wilkie-Grantham RP, Matsuzawa S, Reed JC. Novel phosphorylation and ubiquitination sites regulate reactive oxygen species-dependent degradation of anti-apoptotic c-FLIP protein. J Biol Chem. 2013;288:12777–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zheng Z, et al. c-FLIP is involved in tumor progression of peripheral T-cell lymphoma and targeted by histone deacetylase inhibitors. J Hematol Oncol. 2014;7:88.

    Article  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Facultés de Médecine et de Pharmacie, INSERM UMR866, UFR des Sciences de Santé, LNC, Lipides Nutrition Cancer, Room 326, 7 Bd Jeanne d’Arc, 21078/F21079, Dljon, France

    Olivier Micheau

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  1. Olivier Micheau
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Correspondence to Olivier Micheau .

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  1. Georgetown University Div. Hematology & Oncology, Washington, District of Columbia, USA

    John L. Marshall

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Micheau, O. (2015). FLIP. In: Marshall, J. (eds) Cancer Therapeutic Targets. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6613-0_90-1

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  • DOI: https://doi.org/10.1007/978-1-4614-6613-0_90-1

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  • Online ISBN: 978-1-4614-6613-0

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