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Glucocorticoid receptor antagonist sensitizes TRAIL-induced apoptosis in renal carcinoma cells through up-regulation of DR5 and down-regulation of c-FLIP(L) and Bcl-2

Authors
Min, KJ; Jang, JH; Lee, JT; Choi, KS; Kwon, TK
Citation
Journal of molecular medicine, 90(3):309-319, 2012
Journal Title
Journal of molecular medicine
ISSN
0377-046X
Abstract
RU486 (Mifepristone) has been known as antiprogesterone and antiglucocorticoid agent. RU486 is also used for treatment of several cancers, such as breast, ovarian, prostate, and glaucoma. Here, we investigated the effect of RU486 on TRAIL-induced apoptosis in human renal carcinoma Caki cells. Low dose of RU486 (30-50 μM) alone had no effect on apoptosis, but RU486 markedly sensitized Caki cells to TRAIL-induced apoptosis. We found that up-regulation of death receptor 5 (DR5; receptor for TRAIL ligand), and down-regulation of Bcl-2 and c-FLIP (caspase regulator) contributes to RU-486 induced TRAIL sensitization. Down-regulation of DR5 by siRNA also blocked RU486 induced TRAIL sensitization. Furthermore, overexpression of Bcl-1 or c-FLIP(L) inhibited the cell death induced by the combined treatment with RU486 and TRAIL. RU486 increased DR5 expression at the transcriptional levels through induction of CHOP expression. By contrast, RU486 did not sensitize normal human mesangial cells to TRAIL-mediated apoptosis. Effect of RU486 on TRAIL-induced cancer cell apoptosis was independent of glucocorticoid receptor and progesterone receptor. Taken together, RU486 enhances TRAIL-mediated apoptosis through down-regulation of Bcl-2 and c-FLIP(L) as well as CHOP-mediated DR5 up-regulation.
MeSH terms
Apoptosis/*drug effectsCASP8 and FADD-Like Apoptosis Regulating Protein/*drug effects/genetics/metabolismCarcinoma, Renal Cell/*metabolism/pathologyCell LineDown-RegulationHT29 CellsHumansMesangial Cells/metabolism/pathologyMifepristone/*pharmacologyProto-Oncogene Proteins c-bcl-2/*drug effects/genetics/metabolismReceptors, Glucocorticoid/antagonists & inhibitorsReceptors, TNF-Related Apoptosis-Inducing Ligand/*drug effects/genetics/metabolismTNF-Related Apoptosis-Inducing Ligand/*drug effects/metabolism/pharmacologyTranscription Factor CHOP/*drug effects/genetics/metabolism/pharmacologyUp-Regulation
DOI
10.1007/s00109-011-0821-8
PMID
22008998
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
최, 경숙
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