title: RU486 Induces Pro-Apoptotic Endoplasmic Reticulum Stress Through the Induction of CHOP Expression by Enhancing C/EBPδ Expression in Human Renal Carcinoma Caki Cells.
abstract: 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.
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea.
authors.forename: Kyoung-jin
authors.initials: KJ
authors.lastname: Min
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea.
authors.forename: Shin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea.
authors.forename: Jong-Wook
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea.
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms; D020935:MAP Kinase Signaling System; D015735:Mifepristone / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012326:RNA Splicing; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D000071717:X-Box Binding Protein 1
chemical_list: D000970:Antineoplastic Agents; C497252:CEBPD protein, human; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D051743:CCAAT-Enhancer-Binding Protein-delta; D051742:Transcription Factor CHOP; D015735:Mifepristone
keywords: APOPTOSIS; C/EBPδ; CHOP; ER STRESS; RU486