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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
Published on: December 19, 2018
Effect of anti-estrogens on the androgen receptor activity and cell proliferation in prostate cancer cells
Hidenori Kawashima1, Tomoaki Tanaka, Jed-Sian Cheng
1Department of Urology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abenoku, Osaka 545-8585, Japan. hidenori@msic.med.osaka-cu.ac.jp
Abstract:
Although some anti-estrogens have been reported to inhibit the proliferation of prostate cancer cells, few studies on the mechanism by which they suppress the growth of prostate cancer have been reported. We investigated, for the first time, whether anti-estrogens modulate the transactivation activity of the androgen receptor (AR) in prostate cancer cells. In DU-145 cells transfected with AR, the transactivation activity of AR was inhibited by tamoxifen and toremifene, even in the presence of 10 nM of DHT. On the other hand, in LNCaP cells having an endogenous AR mutation at codon 877, the activity of AR was suppressed by faslodex in the presence of 10 nM DHT, whereas it was not inhibited by tamoxifen nor toremifene. In PC-3 cells, both the cell growth and the AR activity were remarkably inhibited by tamoxifen at 50 microM. Faslodex and toremifene inhibited AR activity to some extent, but they seemed to function as agonists at higher concentrations. In PC-3 cells, the inhibition of cell growth by flutamide, faslodex and toremifene was much less than their suppression of AR activity. We also demonstrated that a synthetic estrogen diethylstilbestrol and progesterone-related drugs such as chlormadinone acetate and allylestrenol dose-dependently inhibited the activity of AR in DU-145 and PC-3 cells. These results highlight the anti-androgenic aspect of anti-estrogens and estrogens in regard to the AR-mediated transcription of the relevant genes in prostate cancer.
Insights
Anti-estrogens and estrogens can suppress prostate cancer growth by inhibiting androgen receptor (AR) activity. This study reveals their anti-androgenic effects, impacting AR-mediated gene transcription in prostate cancer cells.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Prostate cancer growth is often driven by the androgen receptor (AR).
- While some anti-estrogens inhibit prostate cancer cell proliferation, their mechanisms remain underexplored.
- The modulation of AR transactivation by anti-estrogens is a key area for investigation.
Purpose of the Study:
- To investigate the effect of anti-estrogens on androgen receptor (AR) transactivation in prostate cancer cells.
- To elucidate the anti-androgenic mechanisms of various compounds in prostate cancer.
Main Methods:
- Utilized prostate cancer cell lines (DU-145, LNCaP, PC-3) with varying AR statuses.
- Assessed AR transactivation activity in response to anti-estrogens, estrogens, and progestins.
- Measured cell growth inhibition in conjunction with AR activity suppression.
Main Results:
- Tamoxifen and toremifene inhibited AR activity in AR-transfected DU-145 cells.
- Faslodex suppressed AR activity in LNCaP cells with a mutated AR, while tamoxifen and toremifene did not.
- Tamoxifen inhibited both cell growth and AR activity in PC-3 cells; other agents showed varied effects, sometimes acting as agonists at higher concentrations.
- Estrogens and progestins also demonstrated dose-dependent inhibition of AR activity.
Conclusions:
- Anti-estrogens and estrogens exhibit anti-androgenic properties by modulating AR-mediated transcription.
- These findings highlight a potential therapeutic avenue targeting AR signaling in prostate cancer.
