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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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CASP8 and FADD-Like Apoptosis Regulating Protein / drug effects*
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
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Carcinoma, Renal Cell / metabolism*
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Carcinoma, Renal Cell / pathology
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Cell Line
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Down-Regulation
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HT29 Cells
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Humans
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Mesangial Cells / metabolism
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Mesangial Cells / pathology
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Mifepristone / pharmacology*
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Proto-Oncogene Proteins c-bcl-2 / drug effects*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptors, Glucocorticoid / antagonists & inhibitors
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Receptors, TNF-Related Apoptosis-Inducing Ligand / drug effects*
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Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
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TNF-Related Apoptosis-Inducing Ligand / drug effects*
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TNF-Related Apoptosis-Inducing Ligand / metabolism
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TNF-Related Apoptosis-Inducing Ligand / pharmacology
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Transcription Factor CHOP / drug effects*
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Transcription Factor CHOP / genetics
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Transcription Factor CHOP / metabolism
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Transcription Factor CHOP / pharmacology
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Up-Regulation
Substances
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Glucocorticoid
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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TNF-Related Apoptosis-Inducing Ligand
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Transcription Factor CHOP
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Mifepristone