Antagonism of androgen action in prostate tumor cells by retinoic acid.
Recent studies have demonstrated that retinoic acid (RA) can repress the growth of human prostatic epithelial cells. Since the proliferation of prostate cells is highly dependent on androgen stimulation, presumably via its cognate receptor, we investigated the effects of RA on the expression of the androgen receptor and other androgen-regulated genes in the human prostatic adenocarcinoma cell line LNCaP. Using a radioligand binding assay, we found that androgen-binding activity was reduced 30-40% in cells treated with 10(-5) M RA plus 6 nM dihydrotestosterone (DHT), as compared to cells with the androgen alone. Moreover, the reduction of the androgen receptor (AR) was not accompanied by alteration of the ligand-binding affinity. Concomitant changes in the function of AR were manifested by a dramatic reduction in AR-mediated transcription activity in a transfection experiment. Androgen-induced levels of both prostate-specific antigen (PSA) and human glandular kallikrein-1 (hKLK2) mRNAs were significantly repressed by RA in a dose- and time-dependent manner. Consistent with this finding, androgen induction of PSA glycoprotein was also repressed by RA, with maximal inhibition occurring at 10(-5) M. These data suggest that the suppression of proliferation and function of prostatic cells by RA may be via modulatory effects on the AR.
Young
C Y
CY
Department of Urology, Mayo Clinic/Foundation, Rochester, Minnesota 55905.
Murtha
P E
PE
Andrews
P E
PE
Lindzey
J K
JK
Tindall
D J
DJ
D000230:Adenocarcinoma / Q000378:metabolism; D000726:Androgen Antagonists / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D009693:Nucleic Acid Hybridization; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000187:drug effects; D011869:Radioligand Assay; D011944:Receptors, Androgen / Q000032:analysis / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; D014212:Tretinoin