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

H G van der Poel1

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

European Urology
|November 1, 2005
PubMed
Abstract

Insights

Androgen receptor (AR) overexpression in hormone refractory prostate cancer (HRPC) cells helps them overcome growth inhibition from transforming growth factor beta 1 (TGFbeta1). This explains how AR supports HRPC growth, even without DHT.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Androgen receptor (AR) and transforming growth factor beta 1 (TGFbeta1) signaling are often overexpressed in hormone refractory prostate cancer (HRPC).
  • AR is known to modulate TGFbeta1/Smad signaling pathways.

Purpose of the Study:

  • To evaluate the role of AR in the response to TGFbeta1 in human prostate cancer cell lines.
  • To understand the interplay between AR and TGFbeta1/Smad signaling in HRPC.

Main Methods:

  • Utilized PC3 (AR-negative) and LNCaP-R2 (AR-expressing) prostate cancer cell lines.
  • Performed luciferase reporter assays for AR, TGFbeta1/Smad, and E2F activity.
  • Assessed cell growth, apoptosis, and c-Myc expression following treatment with dihydrotestosterone (DHT) or TGFbeta1.

Main Results:

  • AR and TGFbeta1/Smad signaling mutually inhibited each other transcriptionally.
  • AR expression reduced TGFbeta1/Smad activity and TGFbeta1's growth-inhibitory effects, independent of DHT.
  • TGFbeta1 reduced AR-mediated E2F activity and c-Myc expression, but AR expression prevented TGFbeta1-induced growth inhibition and apoptosis.

Conclusions:

  • AR overexpression enables HRPC cells to resist TGFbeta1-induced growth inhibition, even with elevated TGFbeta1 levels and without DHT.
  • This mechanism provides a rationale for AR's role in promoting HRPC progression.

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