17beta-estradiol induces apoptosis in the developing rodent prostate independently of ERalpha or ERbeta.
Estrogens induce both proliferative and antiproliferative responses in the prostate gland. To date, antiproliferative effects of estrogens are generally considered to be due to systemic antiandrogenic actions. However, estrogen action mediated through estrogen receptor (ER) beta was recently suggested as another mechanism of induction of apoptosis in the prostate. This study aimed to explore the hypothesis that the antiproliferative effects of estrogen are directly mediated through ERbeta using a prostate organ culture system. We previously reported effects of 17beta-estradiol (E2) using rat ventral prostate (VP) tissues, and adapted the system for culturing mouse tissues. In both rat and mouse models, estrogen-induced apoptosis was detected that was spatially and regionally localized to the epithelium of the distal tips. Using organ cultures of alphaER knockout (alphaERKO) and betaERKO prostates, we failed to demonstrate that apoptosis induced by E2 was mediated through either receptor subtype. Activation of ER-selective ligands (ERalpha, propyl pyrazole triol, ERbeta, diaryl-proprionitrile, and 5alpha-androstane-3beta,17beta-diol) in organ culture experiments failed to induce apoptosis, as did the membrane impermeable conjugate E2:BSA, discounting the possibility of nongenomic effects. Consequently, E2 regulation of androgen receptor (AR) expression was examined and, in the presence of nanomolar testosterone levels, E2 caused a specific reduction in AR protein expression in wild-type, alphaERKO, and betaERKO mice, particularly in the distal region where apoptosis was detected. This down-regulation of AR protein provides a possible mechanism for the proapoptotic action of E2 that is independent of ERs or nongenomic effects.
Taylor
R A
RA
Monash Institute of Reproduction and Development, Monash University, Clayton, Victoria 3168, Australia.
Cowin
P
P
Couse
J F
JF
Korach
K S
KS
Risbridger
G P
GP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D011467:Prostate / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051381:Rats
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004958:Estradiol