TGF-beta signaling and androgen receptor status determine apoptotic cross-talk in human prostate cancer cells.
BACKGROUND
A signaling interaction between transforming growth factor-beta (TGF-beta) and androgens promotes apoptosis in human prostate cancer cells LNCaP-TbetaRII (androgen-sensitive and TGF-beta responsive). This study investigated the contribution of androgen receptor (AR) in the combined effect of TGF-beta and dihydrotestosterone (DHT), on regulation of apoptosis and AR- and TGF-beta mediated transcriptional activity in human prostate cancer cells.


METHODS
Transcriptional activation in response to TGF-beta (5 ng/ml) and DHT (1 nM) was evaluated using transient transfections and luciferase assays in human prostate cancer cells, LNCaP-TbetaRII and PC-3, overexpressing the wild type AR. The apoptotic response to DHT/TGFbeta treatment was correlated with AR cellular distribution and the AR interaction with TGF-beta intracellular effector Smad4.


RESULTS
The results revealed that TGF-beta signaling induced AR-mediated transcriptional activation in two androgen-responsive promoters [probasin and prostate specific antigen (PSA)]. TGF-beta1 induced transcriptional activity enhanced by DHT in both cell lines (LNCaP-TbetaRII and PC-3-AR) via AR-Smad4 interaction. This interaction however does not exclusively drive TGF-beta mediated apoptosis as DHT failed to enhance such an effect in PC-3 AR (wt) cells.


CONCLUSIONS
These results demonstrate that the AR status determines the sensitivity of prostate cancer cells to the apoptotic effects of TGF-beta1, thus providing a new insight into the mechanism via which TGF-beta cross-sections the AR axis toward the functional convergence of the two pathways in the development of androgen-independent prostate cancer. This study is potentially significant in defining the contribution of AR status to the emergence of androgen-independent prostate tumors.
Zhu
Meng-Lei
ML
Division of Urology, Department of Surgery, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
Partin
James V
JV
Bruckheimer
Elizabeth M
EM
Strup
Stephen E
SE
Kyprianou
Natasha
N
D000727:Androgen-Binding Protein / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
C410798:AR protein, human; D000727:Androgen-Binding Protein; D011944:Receptors, Androgen; D018125:Receptors, Transforming Growth Factor beta; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C027519:probasin; D013196:Dihydrotestosterone; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II