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

Ahmad Safa, Travis W. Day, Ching Huang Wu

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

Cellular FLICE-like inhibitory protein (c-FLIP) has been identified as a protease-dead, procaspase-8-like regulator of death ligand-induced apoptosis, based on observations that c-FLIP impedes tumor necrosis factor-α (TNF-α), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by binding to FADD and/or caspase-8 or -10 in a ligand-dependent fashion, which in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIP is a family of alternatively spliced variants, and primarily exists as long (c-FLIP L) and short (c-FLIPS) splice variants in human cells. Although c-FLIP has apoptogenic activity in some cell contexts, which is currently attributed to heterodimerization with caspase-8 at the DISC, accumulating evidence indicates an anti-apoptotic role for c-FLIP in various types of human cancers. For example, small interfering RNAs (siRNAs) that specifically knocked down expression of c-FLIPL in diverse human cancer cell lines, e.g., lung and cervical cancer cells, augmented TRAIL-induced DISC recruitment, and thereby enhanced effector caspase stimulation and apoptosis. Therefore, the outlook for the therapeutic index of c-FLIP-targeted drugs appears excellent, not only from the efficacy observed in experimental models of cancer therapy, but also because the current understanding of dual c-FLIP action in normal tissues supports the notion that c-FLIP-targeted cancer therapy will be well tolerated. Interestingly, Taxol, TRAIL, as well as several classes of small molecules induce c-FLIP downregulation in neoplastic cells. Efforts are underway to develop small-molecule drugs that induce c-FLIP downregulation and other c-FLIP-targeted cancer therapies. In this review, we assess the outlook for improving cancer therapy through c-FLIP-targeted therapeutics.

Original languageEnglish
Pages (from-to)37-46
Number of pages10
JournalCurrent Cancer Drug Targets
Volume8
Issue number1
DOIs
StatePublished - Feb 2008

Fingerprint

CASP8 and FADD-Like Apoptosis Regulating Protein
Staphylococcal Protein A
Neoplasms
Death Domain Receptor Signaling Adaptor Proteins
Caspase 8
Therapeutics
TNF-Related Apoptosis-Inducing Ligand
Apoptosis
Ligands
Down-Regulation
Tumor Necrosis Factor-alpha
Effector Caspases
Caspases
Paclitaxel

Keywords

  • Apoptosis
  • c-FLIP
  • Caspase-10
  • Caspase-8
  • Death receptors
  • Leukemia
  • Taxol

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Cancer Research

Cite this

Cellular FLICE-like inhibitory protein (C-FLIP) : A novel target for cancer therapy. / Safa, Ahmad; Day, Travis W.; Wu, Ching Huang.

In: Current Cancer Drug Targets, Vol. 8, No. 1, 02.2008, p. 37-46.

Research output: Contribution to journalArticle

@article{4e9f013cb76c4a9fb08900d2729ef536,
title = "Cellular FLICE-like inhibitory protein (C-FLIP): A novel target for cancer therapy",
abstract = "Cellular FLICE-like inhibitory protein (c-FLIP) has been identified as a protease-dead, procaspase-8-like regulator of death ligand-induced apoptosis, based on observations that c-FLIP impedes tumor necrosis factor-α (TNF-α), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by binding to FADD and/or caspase-8 or -10 in a ligand-dependent fashion, which in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIP is a family of alternatively spliced variants, and primarily exists as long (c-FLIP L) and short (c-FLIPS) splice variants in human cells. Although c-FLIP has apoptogenic activity in some cell contexts, which is currently attributed to heterodimerization with caspase-8 at the DISC, accumulating evidence indicates an anti-apoptotic role for c-FLIP in various types of human cancers. For example, small interfering RNAs (siRNAs) that specifically knocked down expression of c-FLIPL in diverse human cancer cell lines, e.g., lung and cervical cancer cells, augmented TRAIL-induced DISC recruitment, and thereby enhanced effector caspase stimulation and apoptosis. Therefore, the outlook for the therapeutic index of c-FLIP-targeted drugs appears excellent, not only from the efficacy observed in experimental models of cancer therapy, but also because the current understanding of dual c-FLIP action in normal tissues supports the notion that c-FLIP-targeted cancer therapy will be well tolerated. Interestingly, Taxol, TRAIL, as well as several classes of small molecules induce c-FLIP downregulation in neoplastic cells. Efforts are underway to develop small-molecule drugs that induce c-FLIP downregulation and other c-FLIP-targeted cancer therapies. In this review, we assess the outlook for improving cancer therapy through c-FLIP-targeted therapeutics.",
keywords = "Apoptosis, c-FLIP, Caspase-10, Caspase-8, Death receptors, Leukemia, Taxol",
author = "Ahmad Safa and Day, {Travis W.} and Wu, {Ching Huang}",
year = "2008",
month = "2",
doi = "10.2174/156800908783497087",
language = "English",
volume = "8",
pages = "37--46",
journal = "Current Cancer Drug Targets",
issn = "1568-0096",
publisher = "Bentham Science Publishers B.V.",
number = "1",

}

TY - JOUR

T1 - Cellular FLICE-like inhibitory protein (C-FLIP)

T2 - A novel target for cancer therapy

AU - Safa, Ahmad

AU - Day, Travis W.

AU - Wu, Ching Huang

PY - 2008/2

Y1 - 2008/2

N2 - Cellular FLICE-like inhibitory protein (c-FLIP) has been identified as a protease-dead, procaspase-8-like regulator of death ligand-induced apoptosis, based on observations that c-FLIP impedes tumor necrosis factor-α (TNF-α), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by binding to FADD and/or caspase-8 or -10 in a ligand-dependent fashion, which in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIP is a family of alternatively spliced variants, and primarily exists as long (c-FLIP L) and short (c-FLIPS) splice variants in human cells. Although c-FLIP has apoptogenic activity in some cell contexts, which is currently attributed to heterodimerization with caspase-8 at the DISC, accumulating evidence indicates an anti-apoptotic role for c-FLIP in various types of human cancers. For example, small interfering RNAs (siRNAs) that specifically knocked down expression of c-FLIPL in diverse human cancer cell lines, e.g., lung and cervical cancer cells, augmented TRAIL-induced DISC recruitment, and thereby enhanced effector caspase stimulation and apoptosis. Therefore, the outlook for the therapeutic index of c-FLIP-targeted drugs appears excellent, not only from the efficacy observed in experimental models of cancer therapy, but also because the current understanding of dual c-FLIP action in normal tissues supports the notion that c-FLIP-targeted cancer therapy will be well tolerated. Interestingly, Taxol, TRAIL, as well as several classes of small molecules induce c-FLIP downregulation in neoplastic cells. Efforts are underway to develop small-molecule drugs that induce c-FLIP downregulation and other c-FLIP-targeted cancer therapies. In this review, we assess the outlook for improving cancer therapy through c-FLIP-targeted therapeutics.

AB - Cellular FLICE-like inhibitory protein (c-FLIP) has been identified as a protease-dead, procaspase-8-like regulator of death ligand-induced apoptosis, based on observations that c-FLIP impedes tumor necrosis factor-α (TNF-α), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by binding to FADD and/or caspase-8 or -10 in a ligand-dependent fashion, which in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIP is a family of alternatively spliced variants, and primarily exists as long (c-FLIP L) and short (c-FLIPS) splice variants in human cells. Although c-FLIP has apoptogenic activity in some cell contexts, which is currently attributed to heterodimerization with caspase-8 at the DISC, accumulating evidence indicates an anti-apoptotic role for c-FLIP in various types of human cancers. For example, small interfering RNAs (siRNAs) that specifically knocked down expression of c-FLIPL in diverse human cancer cell lines, e.g., lung and cervical cancer cells, augmented TRAIL-induced DISC recruitment, and thereby enhanced effector caspase stimulation and apoptosis. Therefore, the outlook for the therapeutic index of c-FLIP-targeted drugs appears excellent, not only from the efficacy observed in experimental models of cancer therapy, but also because the current understanding of dual c-FLIP action in normal tissues supports the notion that c-FLIP-targeted cancer therapy will be well tolerated. Interestingly, Taxol, TRAIL, as well as several classes of small molecules induce c-FLIP downregulation in neoplastic cells. Efforts are underway to develop small-molecule drugs that induce c-FLIP downregulation and other c-FLIP-targeted cancer therapies. In this review, we assess the outlook for improving cancer therapy through c-FLIP-targeted therapeutics.

KW - Apoptosis

KW - c-FLIP

KW - Caspase-10

KW - Caspase-8

KW - Death receptors

KW - Leukemia

KW - Taxol

UR - http://www.scopus.com/inward/record.url?scp=39049148397&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=39049148397&partnerID=8YFLogxK

U2 - 10.2174/156800908783497087

DO - 10.2174/156800908783497087

M3 - Article

C2 - 18288942

AN - SCOPUS:39049148397

VL - 8

SP - 37

EP - 46

JO - Current Cancer Drug Targets

JF - Current Cancer Drug Targets

SN - 1568-0096

IS - 1

ER -