ANTAGONISM OF ANDROGEN ACTION IN PROSTATE TUMOR-CELLS BY RETINOIC ACID

Recent studies have demonstrated that retinoic acid (RA) can repress t he growth of human prostatic epithelial cells. Since the proliferation of prostate cells is highly dependent on androgen stimulation, presum ably via its cognate receptor, we investigated the effects of RA on th e expression of the androgen receptor and other androgen-regulated gen es in the human prostatic adenocarcinoma cell line LNCaP. Using a radi oligand binding assay, we found that androgen-binding activity was red uced 30-40% in cells treated with 10(-5) M RA plus 6 nM dihydrotestost erone (DHT), as compared to cells with the androgen alone. Moreover, t he reduction of the androgen receptor (AR) was not accompanied by alte ration of the ligand-binding affinity. Concomitant changes in the func tion of AR were manifested by a dramatic reduction in AR-mediated tran scription activity in a transfection experiment. Androgen-induced leve ls of both prostate-specific antigen (PSA) and human glandular kallikr ein-1 (hKLK2) mRNAs were significantly repressed by RA in a dose- and time-dependent manner. Consistent with this finding, androgen inductio n of PSA glycoprotein was also repressed by RA, with maximal inhibitio n occuring at 10(-5) M. These data suggest that the suppression of pro liferation and function of prostatic cells by RA may be via modulatory effects on the AR. (C) 1994 Wiley-Liss, Inc.