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Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy.

Safa AR - J Carcinog Mutagen (2013)

Bottom Line: The Ripoptosome contains receptor-interacting protein-1/Receptor-Interacting Protein-3 (RIP1), caspase-8, caspase-10, FADD, and c-FLIP isoforms involved in switching apoptotic and necroptotic cell death. c-FLIP regulates the Ripoptosome; in addition to its role in apoptosis, it is therefore also involved in necrosis. c-FLIPL attenuates autophagy by direct acting on the autophagy machinery by competing with Atg3 binding to LC3, thereby decreasing LC3 processing and inhibiting autophagosome formation.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, IN 46202, USA ; Indiana University Simon Cancer Center, Indiana University School of Medicine, IN 46202, USA.

ABSTRACT
Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a major antiapoptotic protein and an important cytokine and chemotherapy resistance factor that suppresses cytokine- and chemotherapy-induced apoptosis. 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). 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-κB. In addition to its role in apoptosis, c-FLIP is involved in programmed necroptosis (necrosis) and autophagy. Necroptosis is regulated by the Ripoptosome, which is a signaling intracellular cell death platform complex. The Ripoptosome contains receptor-interacting protein-1/Receptor-Interacting Protein-3 (RIP1), caspase-8, caspase-10, FADD, and c-FLIP isoforms involved in switching apoptotic and necroptotic cell death. c-FLIP regulates the Ripoptosome; in addition to its role in apoptosis, it is therefore also involved in necrosis. c-FLIPL attenuates autophagy by direct acting on the autophagy machinery by competing with Atg3 binding to LC3, thereby decreasing LC3 processing and inhibiting autophagosome formation. 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. This review focuses on (1) the anti-apoptotic role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and chemotherapy drug resistance, as well as its roles in necrosis and autophagy, and (2) modulation of c-FLIP expression as a means to enhance apoptosis and modulate necrosis and autophagy in cancer cells.

No MeSH data available.


Related in: MedlinePlus

Apoptosis signaling pathways and roles of c-FLIP in preventing apoptosis. Interaction of TRAIL with its receptors DR4 and DR5 or binding of Fas ligand to Fas receptor initiates the death receptor (extrinsic) and subsequently mitochondrial apoptosis signaling pathways through FADD-dependent autocatalytic activation of caspases-8 and -10 and Bid cleavage to truncated Bid. c-FLIP isoforms suppress caspase-8 and -10 activation, therefore preventing the downstream apoptosis cascade.
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Figure 1: Apoptosis signaling pathways and roles of c-FLIP in preventing apoptosis. Interaction of TRAIL with its receptors DR4 and DR5 or binding of Fas ligand to Fas receptor initiates the death receptor (extrinsic) and subsequently mitochondrial apoptosis signaling pathways through FADD-dependent autocatalytic activation of caspases-8 and -10 and Bid cleavage to truncated Bid. c-FLIP isoforms suppress caspase-8 and -10 activation, therefore preventing the downstream apoptosis cascade.

Mentions: Two main signaling pathways, the intrinsic or mitochondrion-initiated pathway and the extrinsic or cell surface death receptors pathway, regulate apoptosis (Figure 1) [1,2,9,10]. In the intrinsic pathway, cytochrome c, apoptosis-inducing factors including Smac/DIABLO, HtrA2/Omi, and Endonuclease G (endoG) are released from the mitochondrial to the cytosol [11,12]. Upon release, cytochrome c and dATP bind to apoptotic proteinase-activating factor-1 (Apaf-1), and this complex along with adenine nucleotides form the apoptosome and promote procaspase-9 autoactivation [12,13,14]. Apoptosome assembly is a crucially important point in the mitochondrial pathway of apoptosis, consisting of a wheel-like heptamer of seven Apaf-1 molecules and seven cytochrome c molecules that bind and activate the initiator caspase-9, which in turn activates caspases-2, -3, -6, -7, -8, and -10 [13,14]. Apoptosis induced by different death stimuli requires direct activation of Bax and BAK at the mitochondria by a member of the Bcl-2 homology domain-3 (BH3)-only family of proteins including Bid, Bim, or PUMA [15]. The various anti- and pro-apoptotic members of the Bcl-2 family form an interactive network that finally regulates the release of apoptosis triggering factors such as cytochrome c to the cytoplasm [16]. This release of cytochrome c is associated with opening the Permeability Transition Pore (PTP) and a collapse of mitochondrial transmembrane potential (Δψm) due to the intake of Ca2+ following its release into the cytosol from the Endoplasmic Reticulum (ER) [9, 17]. In the death receptor-mediated or extrinsic apoptosis pathway (e.g., Fas/Fas ligand interaction, tumor necrosis factor α [(TNF-α)/TNF receptor 1 (TNFR1), or TRAIL/DR5 interaction and cell death], the initiator caspases-8 and -10 activate the downstream caspases including caspases-3, -6, and -7 [10,18,19]. Active caspases-8 and -10 are known to cleave a pro-apoptotic Bcl-2 family member, Bid, and the truncated Bid induces mitochondrial cytochrome c release [19-23], thereby linking the two pathways. After activation, both caspases-8 and -9 activate caspase-3, which in turn cleaves other caspases and many cellular proteins [24-26]. Scaffidi et al. [27,28] also have identified two different CD95 apoptosis signaling cell types, type I and type II. In type I cells, CD95-mediated apoptosis is initiated by large amounts of active caspase-8 formed at the DISC and subsequent direct cleavage of caspase-3. In contrast, in type II cells, very little DISC formation and small amounts of active caspase-8 sufficient to trigger the mitochondrial apoptosis pathway lead to a significant activation of both caspase-8 and caspase-3. Overexpressed Bcl-2 or BclxL only can block apoptosis in type II cells [28]. These authors [28] have shown that several apoptosis-inhibiting or -inducing stimuli only affect apoptosis in type II cells. Interestingly, since c-FLIP acts directly at the DISC, it blocks CD95-mediated apoptosis in both type I and type II cells [28].


Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy.

Safa AR - J Carcinog Mutagen (2013)

Apoptosis signaling pathways and roles of c-FLIP in preventing apoptosis. Interaction of TRAIL with its receptors DR4 and DR5 or binding of Fas ligand to Fas receptor initiates the death receptor (extrinsic) and subsequently mitochondrial apoptosis signaling pathways through FADD-dependent autocatalytic activation of caspases-8 and -10 and Bid cleavage to truncated Bid. c-FLIP isoforms suppress caspase-8 and -10 activation, therefore preventing the downstream apoptosis cascade.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219646&req=5

Figure 1: Apoptosis signaling pathways and roles of c-FLIP in preventing apoptosis. Interaction of TRAIL with its receptors DR4 and DR5 or binding of Fas ligand to Fas receptor initiates the death receptor (extrinsic) and subsequently mitochondrial apoptosis signaling pathways through FADD-dependent autocatalytic activation of caspases-8 and -10 and Bid cleavage to truncated Bid. c-FLIP isoforms suppress caspase-8 and -10 activation, therefore preventing the downstream apoptosis cascade.
Mentions: Two main signaling pathways, the intrinsic or mitochondrion-initiated pathway and the extrinsic or cell surface death receptors pathway, regulate apoptosis (Figure 1) [1,2,9,10]. In the intrinsic pathway, cytochrome c, apoptosis-inducing factors including Smac/DIABLO, HtrA2/Omi, and Endonuclease G (endoG) are released from the mitochondrial to the cytosol [11,12]. Upon release, cytochrome c and dATP bind to apoptotic proteinase-activating factor-1 (Apaf-1), and this complex along with adenine nucleotides form the apoptosome and promote procaspase-9 autoactivation [12,13,14]. Apoptosome assembly is a crucially important point in the mitochondrial pathway of apoptosis, consisting of a wheel-like heptamer of seven Apaf-1 molecules and seven cytochrome c molecules that bind and activate the initiator caspase-9, which in turn activates caspases-2, -3, -6, -7, -8, and -10 [13,14]. Apoptosis induced by different death stimuli requires direct activation of Bax and BAK at the mitochondria by a member of the Bcl-2 homology domain-3 (BH3)-only family of proteins including Bid, Bim, or PUMA [15]. The various anti- and pro-apoptotic members of the Bcl-2 family form an interactive network that finally regulates the release of apoptosis triggering factors such as cytochrome c to the cytoplasm [16]. This release of cytochrome c is associated with opening the Permeability Transition Pore (PTP) and a collapse of mitochondrial transmembrane potential (Δψm) due to the intake of Ca2+ following its release into the cytosol from the Endoplasmic Reticulum (ER) [9, 17]. In the death receptor-mediated or extrinsic apoptosis pathway (e.g., Fas/Fas ligand interaction, tumor necrosis factor α [(TNF-α)/TNF receptor 1 (TNFR1), or TRAIL/DR5 interaction and cell death], the initiator caspases-8 and -10 activate the downstream caspases including caspases-3, -6, and -7 [10,18,19]. Active caspases-8 and -10 are known to cleave a pro-apoptotic Bcl-2 family member, Bid, and the truncated Bid induces mitochondrial cytochrome c release [19-23], thereby linking the two pathways. After activation, both caspases-8 and -9 activate caspase-3, which in turn cleaves other caspases and many cellular proteins [24-26]. Scaffidi et al. [27,28] also have identified two different CD95 apoptosis signaling cell types, type I and type II. In type I cells, CD95-mediated apoptosis is initiated by large amounts of active caspase-8 formed at the DISC and subsequent direct cleavage of caspase-3. In contrast, in type II cells, very little DISC formation and small amounts of active caspase-8 sufficient to trigger the mitochondrial apoptosis pathway lead to a significant activation of both caspase-8 and caspase-3. Overexpressed Bcl-2 or BclxL only can block apoptosis in type II cells [28]. These authors [28] have shown that several apoptosis-inhibiting or -inducing stimuli only affect apoptosis in type II cells. Interestingly, since c-FLIP acts directly at the DISC, it blocks CD95-mediated apoptosis in both type I and type II cells [28].

Bottom Line: The Ripoptosome contains receptor-interacting protein-1/Receptor-Interacting Protein-3 (RIP1), caspase-8, caspase-10, FADD, and c-FLIP isoforms involved in switching apoptotic and necroptotic cell death. c-FLIP regulates the Ripoptosome; in addition to its role in apoptosis, it is therefore also involved in necrosis. c-FLIPL attenuates autophagy by direct acting on the autophagy machinery by competing with Atg3 binding to LC3, thereby decreasing LC3 processing and inhibiting autophagosome formation.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, IN 46202, USA ; Indiana University Simon Cancer Center, Indiana University School of Medicine, IN 46202, USA.

ABSTRACT
Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a major antiapoptotic protein and an important cytokine and chemotherapy resistance factor that suppresses cytokine- and chemotherapy-induced apoptosis. 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). 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-κB. In addition to its role in apoptosis, c-FLIP is involved in programmed necroptosis (necrosis) and autophagy. Necroptosis is regulated by the Ripoptosome, which is a signaling intracellular cell death platform complex. The Ripoptosome contains receptor-interacting protein-1/Receptor-Interacting Protein-3 (RIP1), caspase-8, caspase-10, FADD, and c-FLIP isoforms involved in switching apoptotic and necroptotic cell death. c-FLIP regulates the Ripoptosome; in addition to its role in apoptosis, it is therefore also involved in necrosis. c-FLIPL attenuates autophagy by direct acting on the autophagy machinery by competing with Atg3 binding to LC3, thereby decreasing LC3 processing and inhibiting autophagosome formation. 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. This review focuses on (1) the anti-apoptotic role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and chemotherapy drug resistance, as well as its roles in necrosis and autophagy, and (2) modulation of c-FLIP expression as a means to enhance apoptosis and modulate necrosis and autophagy in cancer cells.

No MeSH data available.


Related in: MedlinePlus