c-FLIP, a master anti-apoptotic regulator

c-FLIP, a master anti-apoptotic regulator

Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a master anti-apoptotic regulator and resistance factor that suppresses tumor necrosis factor-α (TNF-α), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apo­pto­sis, as well as apoptosis triggered by c...

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Published in:Experimental Oncology
Date:2012
Main Author: Safa, A.R.
Format: Article
Language:English
Published: Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України 2012
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Reviews
Online Access:https://nasplib.isofts.kiev.ua/handle/123456789/138732
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Journal Title:Digital Library of Periodicals of National Academy of Sciences of Ukraine
Cite this:c-FLIP, a master anti-apoptotic regulator / A.R. Safa // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 176-184. — Бібліогр.: 97 назв. — англ.

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Digital Library of Periodicals of National Academy of Sciences of Ukraine
id nasplib_isofts_kiev_ua-123456789-138732
record_format dspace
spelling Safa, A.R.
2018-06-19T12:19:16Z
2018-06-19T12:19:16Z
2012
c-FLIP, a master anti-apoptotic regulator / A.R. Safa // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 176-184. — Бібліогр.: 97 назв. — англ.
1812-9269
https://nasplib.isofts.kiev.ua/handle/123456789/138732
Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a master anti-apoptotic regulator and resistance factor that suppresses tumor necrosis factor-α (TNF-α), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apo­pto­sis, as well as apoptosis triggered by chemotherapy agents in malignant cells. c-FLIP is expressed as long (c-FLIPL), short (c-FLIPS), and c-FLIPR splice variants in human cells. c-FLIP binds to FADD and/or caspase-8 or -10 and TRAIL receptor 5 (DR5) in a ligand-dependent and -independent fashion and forms an apoptosis inhibitory complex (AIC). This interaction in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIPL and c-FLIPS are also known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective and pro-survival signaling proteins including Akt, ERK, and NF-kB. Upregulation of c-FLIP has been found in various tumor types, and its silencing has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents. Hence, c-FLIP is an important target for cancer therapy. For example, small interfering RNAs (siRNAs) that specifically knockdown the expression of c-FLIPL in diverse human cancer cell lines augmented TRAIL-induced DISC recruitment and increased the efficacy of chemotherapeutic agents, thereby enhancing effector caspase stimulation and apoptosis. Moreover, small molecules causing degradation of c-FLIP as well as decreasing mRNA and protein levels of c-FLIPL and c-FLIPS splice variants have been found, and much effort is focused on developing other c-FLIP-targeted cancer therapies. This review focuses on (1) the anti-apoptotic role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and chemotherapy drug resistance, (2) the molecular mechanisms and factors that regulate c-FLIP expression, and (3) modulation of c-FLIP expression and function to eliminate cancer cells or increase the efficacy of anticancer agents. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”.
I would like to thank Mary D. Kraeszig for her editorial assistance. The work in the author’s laboratory was supported by research grants from the National Cancer Institute (CA 080734, CA 90878, and CA 101743), Department of Defense (DOD) (OC 06095), and the Indiana University Cancer Center Translational Research Acceleration Collaboration (ITRAC) initiative.
en
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
Experimental Oncology
Reviews
c-FLIP, a master anti-apoptotic regulator
Article
published earlier
institution Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection DSpace DC
title c-FLIP, a master anti-apoptotic regulator
spellingShingle c-FLIP, a master anti-apoptotic regulator
Safa, A.R.
Reviews
title_short c-FLIP, a master anti-apoptotic regulator
title_full c-FLIP, a master anti-apoptotic regulator
title_fullStr c-FLIP, a master anti-apoptotic regulator
title_full_unstemmed c-FLIP, a master anti-apoptotic regulator
title_sort c-flip, a master anti-apoptotic regulator
author Safa, A.R.
author_facet Safa, A.R.
topic Reviews
topic_facet Reviews
publishDate 2012
language English
container_title Experimental Oncology
publisher Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
format Article
description Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a master anti-apoptotic regulator and resistance factor that suppresses tumor necrosis factor-α (TNF-α), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apo­pto­sis, as well as apoptosis triggered by chemotherapy agents in malignant cells. c-FLIP is expressed as long (c-FLIPL), short (c-FLIPS), and c-FLIPR splice variants in human cells. c-FLIP binds to FADD and/or caspase-8 or -10 and TRAIL receptor 5 (DR5) in a ligand-dependent and -independent fashion and forms an apoptosis inhibitory complex (AIC). This interaction in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIPL and c-FLIPS are also known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective and pro-survival signaling proteins including Akt, ERK, and NF-kB. Upregulation of c-FLIP has been found in various tumor types, and its silencing has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents. Hence, c-FLIP is an important target for cancer therapy. For example, small interfering RNAs (siRNAs) that specifically knockdown the expression of c-FLIPL in diverse human cancer cell lines augmented TRAIL-induced DISC recruitment and increased the efficacy of chemotherapeutic agents, thereby enhancing effector caspase stimulation and apoptosis. Moreover, small molecules causing degradation of c-FLIP as well as decreasing mRNA and protein levels of c-FLIPL and c-FLIPS splice variants have been found, and much effort is focused on developing other c-FLIP-targeted cancer therapies. This review focuses on (1) the anti-apoptotic role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and chemotherapy drug resistance, (2) the molecular mechanisms and factors that regulate c-FLIP expression, and (3) modulation of c-FLIP expression and function to eliminate cancer cells or increase the efficacy of anticancer agents. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”.
issn 1812-9269
url https://nasplib.isofts.kiev.ua/handle/123456789/138732
citation_txt c-FLIP, a master anti-apoptotic regulator / A.R. Safa // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 176-184. — Бібліогр.: 97 назв. — англ.
work_keys_str_mv AT safaar cflipamasterantiapoptoticregulator
first_indexed 2025-12-07T16:04:22Z
last_indexed 2025-12-07T16:04:22Z
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