Effect of anti-estrogens on the androgen receptor activity and cell proliferation in prostate cancer cells

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.

Disruption of Androgen and Estrogen Receptor Activity in Prostate Cancer by a Novel Dietary Diterpene Carnosol: Implications for Chemoprevention

“…LNCaP cells were treated with carnosol, flutamide, tamoxifen, carnosol/flutamide, carnosol/tamoxifen, or tamoxifen/flutamide for 24 h. In agreement with other investigators (7, 21–23), we observed an increase in AR and ER-α activity with treatment of flutamide or tamoxifen individually as shown by Western blot analysis in Figure 5C. However, upon co-treatment of flutamide or tamoxifen with carnosol, a decrease in protein expression of AR and ER- α was observed.…”

“…Toremifene has a bimodal effect where it functioned as an antagonist at lower concentrations, however, as the dose was increased, it functioned as an agonist in LNCaP cells (7). Limitations of fulvestrant as a dual AR and ER modulator include 1) the AR antagonist effect is saturable regardless of increasing the dose, 2) it can not bind to the mutated AR (T877) that is found in LNCaP cells, and 3) it did not exhibit any effect in a Phase II clinical trial in castration resistant PCa (8, 9).…”

Androgen action on hepatic vitellogenin synthesis in the eel, Anguilla japonica is suppressed by an androgen receptor antagonist

“…Contradictory to this, in a previous study using European eels which show similar reproductive strategy to the species studied here, authors suggested ER-mediation of androgen action based on the inhibition of androgen action by tamoxifen [12]. Recently, however, tamoxifen has been proved to be not only anti-estrogenic, but also antiandrogenic in some occasions [20]. Furthermore, MT has been shown to have 10,000-100,000 times less affinity for ER than E 2 in a fish [17].…”

Fulvestrant (ICI 182,780) down-regulates androgen receptor expression and diminishes androgenic responses in LNCaP human prostate cancer cells

“…5). Recent studies by Kawashima et al (57) showed that ICI decreased DHT stimulation of the androgen-responsive mouse mammary tumor virus-luciferase reporter in LNCaP cells. ER ligands, including ICI, have been shown to inhibit DHT stimulation of PSA transcriptional activity in PC-3 and DU145 cells cotransfected with AR and ER-a and ER-h expression plasmids (58).…”