Antiandrogens inhibit human androgen receptor‐dependent gene transcription activation in the human prostate cancer cells LNCaP

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Abstract
Human androgen receptor (hAR) is a ligand‐dependent transcription factor that mediates androgen‐induced actions on target tissues. Transfection studies in the human prostate cancer cell line LNCaP examine the ability of dihydrotestosterone (DHT), hydroxyflutamide (HO‐FLU), cyproterone acetate (Cypro.A), and RU 23908‐10 to stimulate or to inhibit the transcription activation of mouse mammary tumor virus‐bacterial chloramphenicol acetyltransferase (MMTV‐CAT). DHT stimulated transcription activation of MMTV‐CAT gene in LNCaP cells in a dose‐dependent manner. HO‐FLU, Cypro.A, and RU 23908‐10, though only partially, also stimulated the transcription activation of MMTV‐CAT. Despite this, 100‐ to 1,000‐fold molar excess of all antiandrogens inhibited the agonistic activity of 10 nM DHT in this system. Receptor binding assays confirmed that HO‐FLU, Cypro.A, and RU 23908‐10 competed with DHT for AR binding in LNCaP cells. Western blot analysis using AR antipeptide antibodies raised in rabbits revealed the presence of two AR protein bands in LNCaP cells, following treatment with antiandrogens. Increasing doses of HO‐FLU stimulated the expression of the 114‐kDa AR by 2.5‐fold, but did not affect the 108‐kDa AR. Increasing doses of Cypr0.A and RU 23908‐10 decreased the levels of both the 114‐kDa and the 108‐kDa AR. Although the exact nature of 108‐kDa and 114‐kDa AR in LNCaP cells is still unknown, these data suggest that the regulatory actions of each individual antiandrogen on AR expression in LNCaP cells may be different.