Androgenic control of transforming growth factor-beta signaling in prostate epithelial cells through transcriptional

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Kyung Song1, Hui Wang, Tracy L Krebs

  • 1Case 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.

Cancer Research
|October 3, 2008
PubMed

Insights

5alpha-dihydrotestosterone (DHT) blocks transforming growth factor-beta (TGF-beta)-induced apoptosis in prostate cells by reducing TGF-beta receptor II levels. This androgenic effect involves Sp1/Sp3 elements, impacting prostate cancer progression.

Area of Science:

  • Molecular Endocrinology
  • Cancer Biology
  • Prostate Cancer Research

Background:

  • Androgen receptor signaling is crucial in prostate cancer.
  • Transforming growth factor-beta (TGF-beta) typically induces apoptosis in prostate epithelial cells.
  • The cross-talk between androgen receptor and TGF-beta pathways is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which androgens, specifically 5alpha-dihydrotestosterone (DHT), interfere with TGF-beta-induced apoptosis in prostate epithelial cells.
  • To present a novel model for androgenic effects on TGF-beta signaling.
  • To investigate the role of TGF-beta receptor II (TbetaRII) in this interaction.

Main Methods:

  • Reporter assays and promoter analysis to study TbetaRII gene regulation.
  • DNA pulldown and electrophoretic mobility shift assays (EMSA) to assess protein-DNA interactions.
  • Western blotting to quantify protein levels (Sp1, TbetaRII, Bcl-xL, cyclin D, caspase-3) and assess apoptosis markers.

Main Results:

  • DHT significantly inhibits TGF-beta-induced apoptosis in prostate epithelial cells.
  • DHT treatment leads to a transcriptional down-regulation of TbetaRII.
  • DHT suppresses the binding of Sp1 to the TbetaRII promoter, associated with reduced Sp1 protein and/or activity.
  • The DHT-mediated decrease in TbetaRII suppresses TGF-beta's ability to down-regulate Bcl-xL and cyclin D, activate caspase-3, and induce apoptosis.

Conclusions:

  • DHT inhibits TGF-beta-induced apoptosis via transcriptional suppression of TbetaRII, mediated by interference with Sp1/Sp3 transcription factors.
  • This mechanism provides insight into androgen-mediated growth control in prostate epithelial cells.
  • Understanding this pathway is critical for comprehending prostate cancer progression towards androgen independence.

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