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Dihydrotestosterone enhances transforming growth factor-beta-induced apoptosis in hormone-sensitive prostate cancer

E M Bruckheimer1, N Kyprianou

  • 1Department of Surgery and Molecular Biology, Division of Urology, University of Maryland School of Medicine, Baltimore 21201, USA.

Endocrinology
|May 18, 2001
PubMed

Insights

Dihydrotestosterone (DHT) enhances transforming growth factor-beta (TGF-beta)-induced apoptosis in prostate cancer cells. This interaction primes cancer cells for apoptosis during hormone therapy by upregulating cell cycle arrest and apoptotic proteins.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Androgens, like dihydrotestosterone (DHT), are crucial for prostate cancer cell survival.
  • Transforming growth factor-beta (TGF-beta) is known to induce apoptosis in various cell types, including prostate cancer cells.
  • The interplay between androgens and TGF-beta in prostate cancer apoptosis is not fully understood.

Purpose of the Study:

  • To investigate the interaction between dihydrotestosterone (DHT) and transforming growth factor-beta (TGF-beta) in prostate cancer cells.
  • To determine if DHT influences TGF-beta-mediated apoptosis.
  • To elucidate the molecular mechanisms underlying any observed interactions.

Main Methods:

  • Utilized a derivative of the hormone-sensitive prostate cancer cell line LNCaP, engineered to express TGF-beta receptor II (LNCaP TGF-beta receptor II cells).
  • Treated cells with TGF-beta in the presence and absence of physiological levels of DHT.
  • Assessed cell cycle arrest and apoptosis induction using molecular markers.
  • Investigated the expression of key cell cycle and apoptosis regulators (p21, procaspase-1, bcl-2, bax, caspase-3).
  • Utilized specific caspase inhibitors (z-YVAD for caspase-1, z-DQMD for caspase-3) to confirm the role of caspase-1.

Main Results:

  • Physiological levels of DHT significantly enhanced TGF-beta-induced cell cycle arrest and apoptosis.
  • This enhancement correlated with increased expression of p21 and procaspase-1, and decreased expression of bcl-2.
  • Apoptosis induction was dependent on caspase-1 activity, as it was inhibited by z-YVAD but not z-DQMD.
  • Expression of bax and caspase-3 remained unchanged.

Conclusions:

  • Androgens, specifically DHT, can enhance TGF-beta-mediated apoptosis in prostate cancer cells.
  • This potentiation involves specific molecular regulators of the cell cycle and apoptosis, including caspase-1.
  • Physiological levels of androgens can stimulate the intrinsic apoptotic potential of prostate cancer cells.
  • These findings provide a molecular basis for priming prostate cancer cells for maximal apoptosis induction during hormone ablation therapy.

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