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Androgen receptor or estrogen receptor‐β blockade alters DHEA‐, DHT‐, and E 2 ‐induced proliferation and PSA production in human prostate cancer cells

2007; Wiley; Volume: 67; Issue: 11 Linguagem: Inglês

10.1002/pros.20585

1097-0045

Julia T. Arnold, Xunxian Liu, Jeffrey D. Allen, Hanh Le, Kimberly K. McFann, Marc R. Blackman,

Prostate Cancer Treatment and Research

Abstract BACKGROUND Dehydroepiandrosterone (DHEA) is an endogenous steroid that is metabolized to androgens and/or estrogens in the human prostate. DHEA levels decline with age, and use of DHEA supplements to retard the aging process is of unproved effectiveness and safety. LNCaP and LAPC‐4 prostate cancer cells were used to determine whether DHEA‐modulated proliferation and prostate specific antigen (PSA) production were mediated via the androgen receptor (AR) and/or ERβ. METHODS Cells were treated with DHEA, DHT, or E 2 and antagonists to AR (Casodex®‐bicalutamide) or ER (ICI 182,780) or siRNA to the respective receptors. Proliferation was assessed by MTT assay and PSA mRNA and protein secretion were measured by quantitative real‐time PCR and ELISA. Associations of AR and ERβ were analyzed by co‐immunoprecipitation studies and fluorescent confocal microscopy. RESULTS DHEA‐, T‐, and E 2 ‐induced proliferation of LNCaP cells was blunted by Casodex but not by ICI treatment. In LNCaP cells, Casodex and ICI suppressed hormone‐induced PSA production. In LAPC‐4 cells, DHT‐stimulated PSA mRNA was inhibited by Casodex and ICI, and the minimal stimulation by DHEA was inhibited by ICI. Use of siRNAs confirmed involvement of AR and ERβ in hormone‐induced PSA production while AR‐ERβ co‐association was suggested by immunoprecipitation and nuclear co‐localization. CONCLUSIONS These findings support involvement of both AR and ERβ in mediating DHEA‐, DHT‐, and E 2 ‐induced PSA expression in prostate cancer cells. Prostate 67: 1152–1162, 2007. © 2007 Wiley‐Liss, Inc.