1283 F-BOX PROTEIN 10, AN NF-KB-DEPENDENT ANTI-APOPTOTIC PROTEIN, REGULATES TRAIL-INDUCED APOPTOSIS THROUGH MODULATING C-FOS/C-FLIP PATHWAY

Abstract

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-jB)-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-Fosdependentpathways.SilencingofFBXL10sensitizes resistantcellstoTRAIL,while,overexpressionofFBXL10repressesTRAILinduced apoptosis. Moreover, our results indicate that expression of FBXL10 functions via an NF-jB-dependent pathway, and TRAIL or proteasome inhibitors downregulate FBXL10 via inhibiting NF-jB 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-jB/FBXL10/c-Fos/ c-FLIP. Therefore, silencing FBXL10 can help overcome resistant cancer cells for pro-apoptotic therapies. Cell Death and Differentiation (2011) 18, 1184–1195; doi:10.1038/cdd.2010.185; published online 21 January 2011