Androgens regulate Hedgehog signalling and proliferation in androgen-dependent prostate cells

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Prostate cancer (PCa) progression is linked to androgen sensitivity and Hedgehog (Hh) pathway activation.
• Aberrations in the Hh pathway are observed during PCa progression to castration-resistant states.
• The precise role of androgen signaling in Hh pathway activation remains unclear.

Purpose of the Study:

• To investigate the direct influence of androgen signaling on the Hedgehog (Hh) pathway in prostate cancer.
• To elucidate the interaction between androgen receptor (AR) signaling and Hh pathway components.

Main Methods:

• Utilized four human prostate cell lines (LNCaP, VCaP, PNT2, PNT2-ARm) with varying AR status.
• Assessed cell proliferation and mRNA expression of Hh pathway members (SHH, IHH, DHH, GLI, PTCH).
• Administered Dihydrotestosterone (DHT), bicalutamide (antiandrogen), and KAAD-cyclopamine (Hh inhibitor).

Main Results:

• KAAD-cyclopamine reduced proliferation in DHT-stimulated cancerous and AR-positive cells.
• DHT downregulated SHH expression in AR-positive cells, an effect reversed by bicalutamide.
• KAAD-cyclopamine inhibited AR activity and, along with bicalutamide, induced GLI and PTCH expression in specific cell lines.

Conclusions:

• Androgen signaling directly regulates Hh pathway activity in prostate cancer.
• DHT-induced inhibition of the Hh pathway is dependent on the androgen receptor (AR).
• The interplay between androgen and Hh pathways is crucial for regulating PCa cell proliferation.