Androgenic control of transforming growth factor-beta signaling in prostate epithelial cells through transcriptional suppression of transforming growth factor-beta receptor II.
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].
Song
Kyung
K
Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA.
Wang
Hui
H
Krebs
Tracy L
TL
Kim
Seong-Jin
SJ
Danielpour
David
D
D000728:Androgens / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D000728:Androgens; C494811:BCL2L1 protein, human; D056741:Cyclin D; D016213:Cyclins; D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; C051321:SERPINE1 protein, human; D016212:Transforming Growth Factor beta; D051020:bcl-X Protein; D013196:Dihydrotestosterone; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D053148:Caspase 3