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RU486 Induces Pro‐Apoptotic Endoplasmic Reticulum Stress Through the Induction of CHOP Expression by Enhancing C/EBPδ Expression in Human Renal Carcinoma Caki Cells

RU486 (Mifepristone) is known as an antagonist of the progesterone receptor and glucocorticoid receptor. Here, we investigated the mechanism underlying anti‐tumor activity of RU486 in renal carcinoma Caki cells. Treatment of Caki cells with RU486 was found to induce several signature ER stress markers; including ER stress‐specific XBP1 splicing, and the up‐regulation of glucose‐regulated protein (GRP)‐78 and CCAAT/enhancer‐binding protein homologous protein (CHOP) expression. RU486‐induced expression of CHOP involves the putative C/EBPδ site within the CHOP promoter region. Using a combination of C/EBPδ cDNA transfection, the luciferase assay with a mutated C/EBPδ binding site and siRNA‐mediated C/EBPδ knockdown, we found that the C/EBPδ site is required for RU486‐mediated activation of the CHOP promoter. In addition, RU486‐induced CHOP expression is down‐regulated by inhibition of the p38 MAPK and JNK signaling pathways at the post‐translational levels. RU486 dose‐dependently induced apoptotic cell death in renal carcinoma cells. Suppression of CHOP expression by CHOP siRNA attenuated RU486‐induced apoptosis. Taken together, RU486 induces pro‐apoptotic ER stress through the induction of CHOP expression. J. Cell. Biochem. 117: 361–369, 2016. © 2015 Wiley Periodicals, Inc.