Cellular FLICE‐inhibitory Protein: An Update

Micheau, Olivier

doi:10.1002/9783527619665.ch4

Cited by 5 publications

(10 citation statements)

References 210 publications

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“…melanoma, osteosarcoma, hepatoma, colon or bladder carcinoma and acute or chronic leukemia [81][82][83][84][85]. c-FLIP is a death effector domain (DED)-containing protein that has homology to caspase-8 and caspase-10, but lacks protease activity [89]. By binding to the death receptor adaptor molecule FADD, c-FLIP prevents the interaction between FADD and pro-caspase-8 [89].…”

Section: C-flipmentioning

confidence: 99%

“…By binding to the death receptor adaptor molecule FADD, c-FLIP prevents the interaction between FADD and pro-caspase-8 [89]. c-FLIP exists as distinct splice variants including a long (c-FLIP L ) and a short isoform (c-FLIP S ), both of which can inhibit death receptor-induced apoptosis [89]. While HDACI are generally regarded as transcriptional activators by acetylation of histone or non-histone proteins, treatment with HDACI resulted in a reduction of c-FLIP expression [81][82][83][84][85].…”

Section: C-flipmentioning

confidence: 99%

“…c-FLIP is a death effector domain (DED)-containing protein that has homology to caspase-8 and caspase-10, but lacks protease activity [89]. By binding to the death receptor adaptor molecule FADD, c-FLIP prevents the interaction between FADD and pro-caspase-8 [89]. c-FLIP exists as distinct splice variants including a long (c-FLIP L ) and a short isoform (c-FLIP S ), both of which can inhibit death receptor-induced apoptosis [89].…”

Section: C-flipmentioning

confidence: 99%

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Modulation of TRAIL-Induced Apoptosis by HDAC Inhibitors

Fulda

2008

CCDT

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Triggering apoptosis, the cell's intrinsic death program, is a promising approach for cancer therapy. TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of death inducing ligands, is of special interest for cancer therapy, since TRAIL has been shown to predominantly kill cancer cells, while sparing normal cells. However, since many cancers fail to undergo apoptosis in response to TRAIL treatment, TRAIL-based combination therapies have been developed for cancer-cell specific sensitization towards TRAIL. Chromatin remodelling plays an important role in gene regulation and aberrant architecture of the chromatin has been implicated in tumor formation and progression. In recent years, HDAC inhibitors (HDACI) that reverse aberrant epigenetic changes have emerged as a potential strategy to sensitize cancer cells for TRAIL-induced apoptosis. Synergistic tumor cell death has been reported in a variety of human cancers using different HDACI together with TRAIL. Here, recent advances in the understanding of the molecular events that underlie the synergistic interaction of HDACI and TRAIL are discussed as well as how this knowledge can be translated into the design of cancer-selective novel therapeutics.

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Section: C-flipmentioning

confidence: 99%

Section: C-flipmentioning

confidence: 99%

Section: C-flipmentioning

confidence: 99%

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Modulation of TRAIL-Induced Apoptosis by HDAC Inhibitors

Fulda

2008

CCDT

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“…7 Apoptosis is controlled by various pro-and anti-apoptotic proteins, for example, members of the Bcl-2 family, 8 inhibitor of apoptosis (IAP) proteins 9 and other proteins like cellular FLICEinhibitory protein (cFLIP). 10 Two major splice variants of cFLIP exist, that is, cFLIP L and cFLIP S , which both can block death-receptor signaling by interfering with caspase-8 activation at the DISC. 10 Recombinant soluble TRAIL and agonistic TRAIL receptor antibodies are considered as promising cancer therapeutics as they have been shown to induce apoptosis in various cancer cells while leaving non-malignant cells unharmed.…”

Section: Introductionmentioning

confidence: 99%

“…10 Two major splice variants of cFLIP exist, that is, cFLIP L and cFLIP S , which both can block death-receptor signaling by interfering with caspase-8 activation at the DISC. 10 Recombinant soluble TRAIL and agonistic TRAIL receptor antibodies are considered as promising cancer therapeutics as they have been shown to induce apoptosis in various cancer cells while leaving non-malignant cells unharmed. 11 However, primary or acquired resistance limits their use as single agents in many cancers including glioblastoma, 12 underscoring the importance of the development of combination treatments.…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP

et al. 2012

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Glioblastoma is the most common primary brain tumor with a very poor prognosis, calling for novel treatment strategies. Here, we provide first evidence that histone deacetylase inhibitors (HDACI) prime glioblastoma cells for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) -induced apoptosis at least in part by c-myc-mediated downregulation of cellular FLICE-inhibitory protein (cFLIP). Pretreatment with distinct HDACI (MS275, suberoylanilide hydroxamic acid, valproic acid) significantly enhances TRAIL-induced apoptosis in several glioblastoma cell lines. Monitoring a panel of apoptosisregulatory proteins revealed that MS275 reduces the expression of cFLIP L and cFLIP S . This leads to decreased recruitment of cFLIP L and cFLIP S and increased activation of caspase-8 to the TRAIL death-inducing signaling complex, resulting in enhanced cleavage of caspase-8, -9 and -3 and caspase-dependent apoptosis. Also, MS275 promotes TRAIL-triggered processing of Bid, activation of Bax, loss of mitochondrial membrane potential and release of cytochrome c. MS275-mediated downregulation of cFLIP occurs at the mRNA level independent of proteasome-or caspase-mediated degradation, and is preceded by upregulation of nuclear levels of c-myc, a transcriptional repressor of cFLIP. Notably, MS275 causes increased binding of c-myc to the cFLIP promoter and reduces cFLIP promoter activity. Indeed, knockdown of c-myc partially rescues cFLIP L from MS275-inferred downregulation and significantly decreases TRAIL-and MS275-induced apoptosis. Also, overexpression of cFLIP L or cFLIP S significantly reduces MS275-and TRAIL-induced apoptosis. Importantly, MS275 sensitizes primary cultured glioblastoma cells towards TRAIL and cooperates with TRAIL to reduce long-term clonogenic survival of glioblastoma cells and to suppress glioblastoma growth in vivo underscoring the clinical relevance of this approach. Thus, these findings demonstrate that HDACI represent a promising strategy to prime glioblastoma for TRAIL-induced apoptosis by targeting cFLIP.

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Targeting c-FLIP in cancer

2013

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Cellular-FLICE inhibitory protein (c-FLIP) is a key anti-apoptotic regulator that inhibits cell death mediated by the death receptors Fas, DR4, DR5, and TNF-R1. Three splice variants of c-FLIP function at the DISC level by blocking the processing and activation of procaspase-8 and -10. Overexpression of c-FLIP has been identified in many different tumour types, and its downregulation in vitro has been shown to restore apoptosis mediated by CD95L and TRAIL. c-FLIP therefore represents a promising target for cancer therapy. This review focuses on the molecular mechanisms that control c-FLIP expression and current research into inhibitors of the protein. Increasing evidence supports the investigation of c-FLIP as a therapeutic target to restore an apoptotic response in cancer cells.

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Cellular FLICE‐inhibitory Protein: An Update

Cited by 5 publications

References 210 publications

Modulation of TRAIL-Induced Apoptosis by HDAC Inhibitors

Modulation of TRAIL-Induced Apoptosis by HDAC Inhibitors

Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP

Targeting c-FLIP in cancer

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