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2012 ; 34
(3
): 176-84
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c-FLIP, a master anti-apoptotic regulator
#MMPMID23070002
Safa AR
Exp Oncol
2012[Oct]; 34
(3
): 176-84
PMID23070002
show ga
Cellular FLICE (FADD-like IL-1?-converting enzyme)-inhibitory protein (c-FLIP) is
a master anti-apoptotic regulator and resistance factor that suppresses tumor
necrosis factor-? (TNF-?), 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-FLIP(L)), short (c-FLIP(S)),
and c-FLIP(R) 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-FLIP(L) and c-FLIP(S) 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-FLIP(L) 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-FLIP(L) and c-FLIP(S)
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".
|*Apoptosis
[MESH]
|*Neoplasms/drug therapy/metabolism
[MESH]
|*Signal Transduction
[MESH]
|Antineoplastic Agents/therapeutic use
[MESH]
|CASP8 and FADD-Like Apoptosis Regulating Protein/*metabolism
[MESH]
|Caspase 8/metabolism
[MESH]
|Drug Resistance, Neoplasm/genetics
[MESH]
|Fas-Associated Death Domain Protein/metabolism
[MESH]
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