Abstract
The androgen receptor cross-talks with transforming growth factor-beta (TGF-beta) through mechanisms that remain poorly understood. Here we provide strong evidence that 5alpha-dihydrotestosterone (DHT) intercepts the ability of prostate epithelial cells to undergo TGF-beta-induced apoptosis, and present a new model for this androgenic effect. We report that DHT decreases the level of TGF-beta receptor II (TbetaRII) through a transcriptional mechanism, leading to suppression of the ability of TGF-beta to down-regulate expression of Bcl-xL and cyclin Ds, activate caspase-3, and induce apoptosis. Promoter analysis, DNA pulldown, and electrophoretic mobility shift assays support that transcriptional down-regulation of TbetaRII by DHT occurs through Sp1/Sp3 response elements, with the binding of Sp1 to the TbetaRII promoter being suppressed by DHT, largely driven by loss of Sp1 protein and/or activity. These results provide fresh insight on the mechanism of growth control by androgens and the progression of prostate cancer to androgen independence. [Cancer Res 2008;68(19):8173-82].
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Androgens / pharmacology*
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Apoptosis / drug effects
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Caspase 3 / metabolism
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Cells, Cultured
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Cyclin D
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Cyclins / genetics
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Cyclins / metabolism
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Cytoprotection / drug effects
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Dihydrotestosterone / pharmacology
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Down-Regulation / drug effects
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Epithelial Cells / drug effects*
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Epithelial Cells / metabolism
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Humans
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Male
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Plasminogen Activator Inhibitor 1 / genetics
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Plasminogen Activator Inhibitor 1 / metabolism
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Prostate / drug effects*
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Prostate / metabolism
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / genetics*
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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Transcription, Genetic / drug effects
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta / pharmacology
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Transforming Growth Factor beta / physiology
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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Androgens
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BCL2L1 protein, human
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Cyclin D
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Cyclins
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Plasminogen Activator Inhibitor 1
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Receptors, Transforming Growth Factor beta
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SERPINE1 protein, human
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Transforming Growth Factor beta
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bcl-X Protein
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Dihydrotestosterone
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II
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Caspase 3