TRANSFORMING GROWTH-FACTOR-BETA-1 INDUCES NUCLEAR TO CYTOPLASMIC DISTRIBUTION OF ANDROGEN RECEPTOR AND INHIBITS ANDROGEN RESPONSE IN PROSTATE SMOOTH-MUSCLE CELLS

Stromal-epithelial interactions in the prostate gland are dependent on androgen regulation of prostate stromal cells, yet little is known ab out androgen action in these cell types. Recent reports have demonstra ted that androgen-regulated gene transcription can be stimulated or in hibited by certain growth factors, indicating crosstalk mechanisms. To address potential cross-talk in signaling pathways between androgen a nd transforming growth factor-beta 1 (TGF beta 1) in prostate stromal cells, the PS-1 prostate smooth muscle cell line was examined. In the presence of physiological concentrations of androgen, PS-1 cell prolif eration was stimulated, and androgen receptor (AR) exhibited a nuclear localization pattern. The addition of TGF beta 1 (25 pM) was capable of blocking androgen-induced proliferation, but had no direct effect i n cultures without androgen. Immunocytochemistry to localize AR subcel lular distribution showed that TGF beta 1 (5-100 par) altered the dist ribution of AR from the nucleus to the cytoplasm. Other growth factors , including fibroblast growth factor-2, epidermal growth factor, and T GF beta 2 had no effect on AR distribution. The TGF beta 1-induced nuc lear to cytoplasmic change in receptor localization was rapid (initiat ed within 30 min), was neutralized by TGF beta 1 antibodies, did not r equire new protein synthesis, and was complete by 6 h. Removal of TGF beta 1 from the culture medium resulted in a rapid redistribution of A R to the nucleus, indicating reversible mechanisms. Northern analysis of the ddp17 marker transcript for androgen action in PS-1 cells showe d that androgen-stimulated ddp17 expression was inhibited in the prese nce of TGF beta 1 (25 pM). TGF beta 1 induced a similar nuclear to cyt oplasmic distribution of AR in primary cultures of rat prostate stroma l cells. TGF beta 1, however, had no effect on AR distribution in eith er the LNCaP prostatic carcinoma cell line or the DDT1MF-8 leiomyosacr oma cell line. Specific cross-talk between TGF beta 1 and AR signaling pathways in prostate stromal cells may play a significant role in pro state development and stromal cell response in carcinoma progression.