Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (cFLIP) is a major anti-apoptotic protein and an important cytokine and chemotherapy resistance factor that suppresses cytokine- and chemotherapy-induced apoptosis.
cFLIP is expressed as long (cFLIPL), short (cFLIPS), and cFLIPR splice variants in human cells. cFLIP 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.
cFLIPL and cFLIPS 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, cFLIP 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 cFLIP isoforms involved in switching apoptotic and necroptotic cell death. cFLIP regulates the Ripoptosome; in addition to its role in apoptosis, it is therefore also involved in necrosis. cFLIPL 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 cFLIP has been found in various tumor types, and its silencing has been shown to restore apoptosis. Therefore, we strongly believe that the cFLIP is an important target for cancer therapy.
Recently, we have investigated and evaluated small interfering RNA candidate that effectively inhibit the expression of cFLIP.
- Compositions for treating or sensitizing interferon beta-resistant cancer comprising cFLIP siRNA (KR, PCT)
- TE Kim et al. Sensitization of glycoengineered interferon-β1a-resistant cancer cells by cFLIP inhibition for enhanced anti-cancer therapy. Oncotarget. 21 (8), 13957–13970. doi:10.18632/oncotarget.14573 (2017)