FLIP: A flop for execution signals

doi:10.1016/j.canlet.2012.07.005

Cancer Letters

Volume 332, Issue 2, 28 May 2013, Pages 151-155

https://doi.org/10.1016/j.canlet.2012.07.005 Get rights and content

Abstract

Resistance to apoptosis is one of the established hallmarks of cancer cells. This is a function of an imbalance between the proteins that facilitate death execution and those that inhibit apoptosis or promote cell proliferation. The anti-apoptotic protein, FLICE inhibitory protein (FLIP), first identified as a viral protein, is over-expressed in a variety of human pathologies. Initial observations linked FLIP expression to inhibition of death receptor induced apoptosis, due to its structural homology to the cysteine protease, caspase-8. FLIP impedes full processing of pro-caspase-8 to its active form and its release to the cytosol, and by doing so blocks apoptotic signaling downstream of the membrane death initiating signaling complex (DISC). Recent observations have highlighted the complex regulation of this protein and its cross talk with diverse signaling networks and metabolic processes. As FLIP expression is directly associated with chemotherapy resistance, a better understanding of its genomic organization, gene transcription, as well as post-transcriptional regulation could yield novel targets with potential therapeutic implications against drug refractory cancers. In this short review, we provide a brief overview of the structural and functional biology of this somewhat complex protein with direct relevance to carcinogenesis.

Highlights

► Resistance to death receptor induced apoptosis. ► cFLIP expression induces death resistance. ► cFLIP as a target for anti-cancer drug development.

Introduction

Escape from normal constraints on growth and proliferation, genomic instability, and resistance to apoptosis are among the hallmarks of cancer [1]. The latter is a function of up regulation of proteins that block apoptosis at different stages of the death execution program. Indeed, a tilt in the intracellular ratio of death promoting proteins and death inhibitory proteins in favor of the latter provides cells with a survival advantage resulting in aberrant proliferation and setting the stage for transformation. Therefore, the past three decades have seen a tremendous increase in interest in understanding the molecular mechanisms underlying the regulation of gene expression, as well as functional biology of the anti-apoptotic effector mechanisms/pathways operative in neoplasia. These efforts have provided insights into novel signaling networks and their regulatory nodes, particularly from the standpoint of genes/proteins that control cell fate decisions.

Section snippets

Apoptosis is a natural tumor suppressor mechanism

Deregulation of apoptotic machinery by suppression and/or decreased expression of pro-apoptotic molecules and/or increased levels of pro-survival proteins is an essential requirement for cancer initiation and progression [2]. Therefore, novel anti-cancer strategies include drugs that reactivate death signaling by specifically targeting anti-apoptotic proteins such as Bcl-2 [3], IAP family [4] and cFLIP (FLICE inhibitory protein [5].

Apoptotic cell death is classified into extrinsic and intrinsic

cFLIP promotes carcinogenesis by regulating apoptotic signaling

The cellular FLICE-inhibitory protein (cFLIP; also referred to as Casper, FLAME-1, CLARP) is the mammalian homolog of the viral cell death regulatory proteins v-FLIPs, and expressed in three different isoforms, namely cFLIP_L (55 kDa), cFLIP_R (24 kDa) and cFLIP_s (26 kDa) [10], [11]. It should be pointed out that the expression of the various isoforms is a function of alternative splicing of the cFLIP gene, which is transcribed under the same promoter. Of note, despite structural differences at the

Genome organization and regulation of cFLIP expression

The genome organization of cFLIP is quite complex as the gene is 50 Kb in length and spatially separated by 10 introns. The promoter region spans about 1.5 Kb upstream of the transcriptional start site and contains numerous transcription factors’ binding sites [16]. Among the several possible transcription factors associated with the activation of cFLIP transcription are AP-1 (c-Fos and c-Jun), CREB, SP1, and NF-kB [10]. In addition, other transcription factor binding sites have been described

Cross talk between cell metabolism and cFLIP

Although, the major point of focus has been the death inhibitory activity of cFLIP, in particular its ability to inhibit death receptor-mediated signaling, recent evidence points to a complex network of pathways involved in the regulation of cFLIP as well as the effect of cFLIP expression on cells’ metabolic activity. For example, the intricate crosstalk between NF-kB signaling and cFLIP expression underscores the importance of this protein in the workings of a “master” regulator of cell

Concluding remarks and unanswered questions

Overexpression of cFLIP isoforms is associated with resistance to death receptor and drug-induced apoptosis. Therefore, targeting cFLIP has been proposed as an attractive strategy for novel anti-cancer drug design. Thus, use of siRNA mediated gene silencing and identification of compounds with the ability to down-regulate cFLIP expression are attractive and logical options. In this regard, a number of small molecule compounds have been shown to sensitize cancer cells via their effect on the

Acknowledgements

We would like to acknowledge all authors whose work may have been omitted due to space constraint. S.P. is supported by grants from The National Medical Research Council, The Biomedical Research Council, The Ministry of Education (Tier 2), and the Cancer Science institute, Singapore. Special thanks to Dr. Gregory Mellier for assistance in preparing the schematic illustration.

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Mini-reviewFLIP: A flop for execution signals

Abstract

Highlights

Introduction

Section snippets

Apoptosis is a natural tumor suppressor mechanism

cFLIP promotes carcinogenesis by regulating apoptotic signaling

Genome organization and regulation of cFLIP expression

Cross talk between cell metabolism and cFLIP

Concluding remarks and unanswered questions

Acknowledgements

Cell

Semin. Immunol.

J. Biol. Chem.

Cancer Lett.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Cell

Curr. Biol.

J. Biol. Chem.

Blood

J. Biol. Chem.

Nitric Oxide

Febs Lett.

Biochem. Biophys. Res. Commun.

Redox. Cell Biol. Genet., Part A

Int. J. Biochem. Cell Biol.

Febs Lett.

Mol. Cell

Mol. Cell

Dysregulation of apoptosis in cancer

J. Clin. Oncol.

Targeting the Bcl-2

Curr. Opin. Oncol.

Targeting survivin in cancer therapy

Expert Opin. Ther. Targets

Targeting the FLICE Inhibitory Protein (FLIP) in cancer therapy

Mol. Interv.

Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy

Oncogene

The Fas-FADD death domain complex structure unravels signalling by receptor clustering

Nature

Cellular FLICE-inhibitory protein: an attractive therapeutic target?

Expert Opin. Ther. Targets

Cellular FLICE-like inhibitory protein (C-FLIP): a novel target for cancer therapy

Curr. Cancer Drug. Targets

FLIP and the death effector domain family

Oncogene

Expression of cellular FLICE inhibitory proteins (cFLIP) in normal and traumatic murine and human cerebral cortex

J. Cereb. Blood Flow. Metab.

Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL

Breast Cancer Res.

Targeting the anti-apoptotic protein c-FLIP for cancer therapy

Cancers (Basel)

Mini-review
FLIP: A flop for execution signals