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Cancers 2011, 3(2), 1639-1671; doi:10.3390/cancers3021639
Review

Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy

1,2,*  and 1,2,3
Received: 26 February 2011; in revised form: 15 March 2011 / Accepted: 16 March 2011 / Published: 29 March 2011
(This article belongs to the Special Issue Cell Death and Cancer)
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Abstract: Cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory protein (c-FLIP) is a major resistance factor and critical anti-apoptotic regulator that inhibits tumor necrosis factor-alpha (TNF-alpha), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis as well as chemotherapy-triggered apoptosis 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 in a ligand-dependent and-independent fashion, which in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. Moreover, c-FLIPL and c-FLIPS are known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective signaling molecules. Upregulation of c-FLIP has been found in various tumor types, and its downregulation 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 efforts are underway to develop other c-FLIP-targeted cancer therapies. This review focuses on (1) the functional role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and drug resistance; (2) the molecular mechanisms that regulate c-FLIP expression; and (3) strategies to inhibit c-FLIP expression and function.
Keywords: c-FLIP; apoptosis; death receptors; cancer; chemotherapy c-FLIP; apoptosis; death receptors; cancer; chemotherapy
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Safa, A.R.; Pollok, K.E. Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy. Cancers 2011, 3, 1639-1671.

AMA Style

Safa AR, Pollok KE. Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy. Cancers. 2011; 3(2):1639-1671.

Chicago/Turabian Style

Safa, Ahmad R.; Pollok, Karen E. 2011. "Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy." Cancers 3, no. 2: 1639-1671.



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