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Transforming Growth Factor-ß1 Induces Nuclear to Cytoplasmic Distribution of Androgen Receptor and Inhibits Androgen Response in Prostate Smooth Muscle Cells¹

Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: David R. Rowley, Ph.D., Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030.

Stromal-epithelial interactions in the prostate gland are dependent on androgen regulation of prostate stromal cells, yet little is known about androgen action in these cell types. Recent reports have demonstrated that androgen-regulated gene transcription can be stimulated or inhibited by certain growth factors, indicating cross-talk mechanisms. To address potential cross-talk in signaling pathways between androgen and transforming growth factor-ß1 (TGFß1) 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 proliferation was stimulated, and androgen receptor (AR) exhibited a nuclear localization pattern. The addition of TGFß1 (25 pM) was capable of blocking androgen-induced proliferation, but had no direct effect in cultures without androgen. Immunocytochemistry to localize AR subcellular distribution showed that TGFß1 (5–100 pM) altered the distribution of AR from the nucleus to the cytoplasm. Other growth factors, including fibroblast growth factor-2, epidermal growth factor, and TGFß2 had no effect on AR distribution. The TGFß1-induced nuclear to cytoplasmic change in receptor localization was rapid (initiated within 30 min), was neutralized by TGFß1 antibodies, did not require new protein synthesis, and was complete by 6 h. Removal of TGFß1 from the culture medium resulted in a rapid redistribution of AR to the nucleus, indicating reversible mechanisms. Northern analysis of the ddp17 marker transcript for androgen action in PS-1 cells showed that androgen-stimulated ddp17 expression was inhibited in the presence of TGFß1 (25 pM). TGFß1 induced a similar nuclear to cytoplasmic distribution of AR in primary cultures of rat prostate stromal cells. TGFß1, however, had no effect on AR distribution in either the LNCaP prostatic carcinoma cell line or the DDT1MF-2 leiomyosacroma cell line. Specific cross-talk between TGFß1 and AR signaling pathways in prostate stromal cells may play a significant role in prostate development and stromal cell response in carcinoma progression.

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