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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

c-FLIPL mediates regulation of autophagy. Upon cellular stress, autophagosome formation can be induced. c-FLIPL attenuates autophagy by directly acting on the autophagy machinery by inhibiting Atg3 binding to LC3, thereby decreasing LC3 processing.
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Figure 4: c-FLIPL mediates regulation of autophagy. Upon cellular stress, autophagosome formation can be induced. c-FLIPL attenuates autophagy by directly acting on the autophagy machinery by inhibiting Atg3 binding to LC3, thereby decreasing LC3 processing.

Mentions: Autophagy is a degradation pathway by which cytoplasmic components including various damaged cytoplasmic organelles and unused long-lived proteins are sequestered in the autophagosomes, which are delivered to the lysosome to form an autolysosome for final degradation (Figure 4). Autophagy as a programmed cell survival mechanism is important in regulating and maintaining several normal human physiological processes [88-90]. Autophagy also is implicated in the pathogenesis of several diseases in human including cancer, neurodegenerative diseases, aging, muscle diseases, infection, and immunological diseases [90-96]. While autophagy can suppress tumor growth, it also enables tumor cells to survive under stress [97]. Suppression of autophagy can also sensitize cancer cells to anticancer therapy [99,100], but under the apoptosis deficiency condition, autophagy can also cause cell death termed “autophagic cell death” [95,100,94].


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

Safa AR - J Carcinog Mutagen (2013)

c-FLIPL mediates regulation of autophagy. Upon cellular stress, autophagosome formation can be induced. c-FLIPL attenuates autophagy by directly acting on the autophagy machinery by inhibiting Atg3 binding to LC3, thereby decreasing LC3 processing.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: c-FLIPL mediates regulation of autophagy. Upon cellular stress, autophagosome formation can be induced. c-FLIPL attenuates autophagy by directly acting on the autophagy machinery by inhibiting Atg3 binding to LC3, thereby decreasing LC3 processing.
Mentions: Autophagy is a degradation pathway by which cytoplasmic components including various damaged cytoplasmic organelles and unused long-lived proteins are sequestered in the autophagosomes, which are delivered to the lysosome to form an autolysosome for final degradation (Figure 4). Autophagy as a programmed cell survival mechanism is important in regulating and maintaining several normal human physiological processes [88-90]. Autophagy also is implicated in the pathogenesis of several diseases in human including cancer, neurodegenerative diseases, aging, muscle diseases, infection, and immunological diseases [90-96]. While autophagy can suppress tumor growth, it also enables tumor cells to survive under stress [97]. Suppression of autophagy can also sensitize cancer cells to anticancer therapy [99,100], but under the apoptosis deficiency condition, autophagy can also cause cell death termed “autophagic cell death” [95,100,94].

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