TGF-β signaling and androgen receptor status determine apoptotic cross-talk in human prostate cancer cells

BACKGROUND A signaling interaction between transforming growth factor‐β (TGF‐β) and androgens promotes apoptosis in human prostate cancer cells LNCaP‐TβRII (androgen‐sensitive and TGF‐β responsive). This study investigated the contribution of androgen receptor (AR) in the combined effect of TGF‐β an...

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Published in:The Prostate 2008-02, Vol.68 (3), p.287-295
Main Authors: Zhu, Meng-Lei, Partin, James V., Bruckheimer, Elizabeth M., Strup, Stephen E., Kyprianou, Natasha
Format: Article
Language:English
Subjects:
androgen receptor
Androgen-Binding Protein - metabolism
androgens
Apoptosis - drug effects
Apoptosis - physiology
Biological and medical sciences
Blotting, Western
Cell Line, Tumor
Dihydrotestosterone - pharmacology
Drug Synergism
Gynecology. Andrology. Obstetrics
hormone independence
Humans
Luciferases - genetics
Luciferases - metabolism
Male
Male genital diseases
Medical sciences
Microscopy, Fluorescence
Neoplasms, Hormone-Dependent - metabolism
Neoplasms, Hormone-Dependent - pathology
Nephrology. Urinary tract diseases
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Protein-Serine-Threonine Kinases - metabolism
Receptors, Androgen - biosynthesis
Receptors, Androgen - genetics
Receptors, Androgen - metabolism
Receptors, Transforming Growth Factor beta - metabolism
Signal Transduction
Smad proteins prostate cancer
Smad4 Protein - metabolism
TGF-β
Transcriptional Activation - drug effects
Transfection
Transforming Growth Factor beta - metabolism
Transforming Growth Factor beta - pharmacology
Tumors
Tumors of the urinary system
Urinary tract. Prostate gland
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Summary:BACKGROUND A signaling interaction between transforming growth factor‐β (TGF‐β) and androgens promotes apoptosis in human prostate cancer cells LNCaP‐TβRII (androgen‐sensitive and TGF‐β responsive). This study investigated the contribution of androgen receptor (AR) in the combined effect of TGF‐β and dihydrotestosterone (DHT), on regulation of apoptosis and AR‐ and TGF‐β mediated transcriptional activity in human prostate cancer cells. METHODS Transcriptional activation in response to TGF‐β (5 ng/ml) and DHT (1 nM) was evaluated using transient transfections and luciferase assays in human prostate cancer cells, LNCaP‐TβRII and PC‐3, overexpressing the wild type AR. The apoptotic response to DHT/TGFβ treatment was correlated with AR cellular distribution and the AR interaction with TGF‐β intracellular effector Smad4. RESULTS The results revealed that TGF‐β signaling induced AR‐mediated transcriptional activation in two androgen‐responsive promoters [probasin and prostate specific antigen (PSA)]. TGF‐β1 induced transcriptional activity enhanced by DHT in both cell lines (LNCaP‐TβRII and PC‐3‐AR) via AR‐Smad4 interaction. This interaction however does not exclusively drive TGF‐β 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‐β1, thus providing a new insight into the mechanism via which TGF‐β 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. Prostate 68: 287–295, 2008. © 2007 Wiley‐Liss, Inc.
ISSN:0270-4137
1097-0045
DOI:10.1002/pros.20698