F-box protein 10, an NF-κB-dependent anti-apoptotic protein, regulates TRAIL-induced apoptosis through modulating c-Fos/c-FLIP pathway.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces selective apoptotic death of human cancer cells while sparing normal human cells. Although TRAIL holds great promise as a potential anticancer agent, some tumors develop resistance to TRAIL. Previously, we have shown that the activator protein 1 (AP-1) family member, c-Fos, is an important modulator of apoptosis. Although F- box protein 10 (FBXL10) has been implicated to regulate an AP-1 family protein, c-Jun, its role in mediating apoptotic pathways has not been previously investigated. Here, we report that FBXL10 is a transcriptional repressor of c-Fos and a target gene of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-p65 in human cancers. We demonstrate that FBXL10 is an important anti-apoptotic molecule, which directly binds and represses c-Fos promoter in order for cancer cells to resist TRAIL-induced apoptosis. FBXL10 indirectly regulates c-FLIP(L) levels via c-Fos-dependent pathways. Silencing of FBXL10 sensitizes resistant cells to TRAIL, while, overexpression of FBXL10 represses TRAIL-induced apoptosis. Moreover, our results indicate that expression of FBXL10 functions via an NF-κB-dependent pathway, and TRAIL or proteasome inhibitors downregulate FBXL10 via inhibiting NF-κB signaling. Taken together, we find a novel functional role for FBXL10 as an anti-apoptotic molecule, and describe a new apoptotic-related pathway that involves NF-κB/FBXL10/c-Fos/c-FLIP. Therefore, silencing FBXL10 can help overcome resistant cancer cells for pro-apoptotic therapies.
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D044783:F-Box Proteins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014183:Transplantation, Heterologous
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D044783:F-Box Proteins; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D051996:Transcription Factor RelA; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; D010089:Oxidoreductases, N-Demethylating; D046988:Proteasome Endopeptidase Complex
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