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Eur Urol. 2005 Dec;48(6):1051-8. Epub 2005 Oct 14.

Androgen receptor and TGFbeta1/Smad signaling are mutually inhibitory in prostate cancer.

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  • 1Department Urology, Netherlands Cancer Institute, Amsterdam. h.vd.poel@nki.nl

Abstract

PURPOSE:

The androgen receptor (AR) has been reported to modulate TGFbeta1/Smad signaling and is, like transforming growth factor beta 1 (TGFbeta1) often overexpressed in hormone refractory prostate cancer (HRPC). In human prostate cancer cell lines the role of AR in the response to TGFbeta1 is evaluated.

MATERIAL AND METHODS:

PC3 cells grow hormone independently, lack AR expression, and have a functioning TGFbeta1/Smad signaling cascade whereas LNCaP cells express (a mutated) AR, and lack TGFbeta receptor (TGFbetaR2) expression. Luciferase reporter assays for AR signaling, TGFbeta1/Smad signaling, and E2F transcriptional activity were performed. PC3 cells and TGFbetaR2 stably-transfected LNCaP cells (LNCaP-R2) were incubated with dihydrotestosterone (DHT), or TGFbeta1. Wst-1 assay and flowcytometric evaluation of annexin-V staining were applied to quantify cell growth and apoptosis. Immunoblot analysis was performed to evaluate c-Myc expression.

RESULTS:

Luciferase reporter assays showed mutual transcriptional inhibition of AR and TGFbeta/Smad signaling in AR transfected PC3 and LNCaP-R2 cells. AR expression reduced the TGFbeta1/Smad transcriptional activity and the growth inhibitory effects of TGFbeta1 also in the absence of DHT in PC3 cells. TGFbeta1 reduced the E2F transcriptional activity of AR activation by DHT. This was associated with a reduced c-Myc expression in PC3 cells. AR expression in PC3 cells prevented TGFbeta1 induced growth inhibition and apoptosis.

CONCLUSION:

AR overexpression is an effective way of hormone refractory prostate cancer cells to overcome the growth inhibitory effects of elevated serum TGFbeta1 levels even in the absence of DHT. These findings provide an explanation for how AR overexpression favors growth in HRPC.

PMID:
16257107
[PubMed - indexed for MEDLINE]
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