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F-box protein 10, a NF-κB-dependent anti-apoptotic protein, regulates TRAIL-induced apoptosis through activation of c-Fos and repression of c-FLIP
Rongbin Ge, M.D., PhD.1, Zongwei Wang, M.D., PhD.1, Qing Zheng, PhD.2, Xiaoyin Xu, PhD.2, Aria F. Olumi, M.D.1.
1Massachusetts General Hospital, Boston, MA, USA, 2Brigham & Women's Hospital, Boston, MA, USA.

BACKGROUND:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes death in cancer cells without killing normal cells. Therefore, TRAIL is the ideal cancer agent with very little cytotoxic effect. However, some cancer cells develop resistance to the pro-apoptotic effects of TRAIL. Here, we demonstrate a novel anti-apoptotic molecule, FBXL10, which regulates TRAIL-induced apoptosis by repressing the c-Fos oncogene by NF-kB mediated pathways.
METHODS:
Prostate, breast and kidney cancer cell lines (PC3, A498 MDA-MB-231 PC3TR and LNCaP) that we have found to be sensitive and resistant to TRAIL-induced apoptosis were used. Luciferase reporter assays were used to assess activity of c-Fos and FBXL-10 promoter regions. Semi-quantitative, RT-PCR, cell viability, Annexin V for apoptosis analysis, Electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) assays were used in vitro. Hydrodynamic transfection was used to assess protein-promoter interactions in-vivo. Orthotopic and subcutaneous tumor xenografts were used for tumor growth analyses.
RESULTS:
We found that FBXL10 is a novel NF-κB dependent anti-apoptotic molecule, which directly binds and represses the 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. We demonstrate a novel functional role for FBXL10 as an anti-apoptotic molecule, and describe a new apoptotic mediated pathway that involves NF-kB/FBXL10/c-Fos/c-FLIP.
CONCLUSIONS:
FBXL10 is a novel anti-apoptotic molecule that regulates TRAIL-induced apoptosis, and silencing FBXL10 can help overcome resistant cancer cells for pro-apoptotic therapies. Identification of molecular pathways that differentiate between sensitive and resistant cancer cells will improve the efficacy of the available pro-apoptotic cancer agents and will lead to identification of new therapies.


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