Regulation of rat prostate stromal cell myodifferentiation by androgen and TGF‐β1

Abstract

BACKGROUND Myodifferentiation of stromal cells is a key step in prostate development and is a hallmark of reactive stroma in prostate cancer. Little is known about regulatory mechanisms, however, prostate stromal cells are androgen‐regulated and TGF‐β1 is a known stimulator of stromal myodifferentiation. The PS‐1 rat prostate stromal cell line expresses androgen receptor, and exhibits androgen‐regulated gene expression and proliferation. TGF‐β1 inhibits androgen action in PS‐1 cells through translocation of androgen receptor from the nucleus to the cytoplasm. The present study was conducted to determine whether myodifferentiation of PS‐1 cells is regulated by androgen and TGF‐β1, and how myodifferentiation affects androgen receptor localization and cell proliferation. METHODS PS‐1 cell cultures were exposed to physiological concentrations of dihydrotestosterone, TGF‐β1, and combinations of both in chemically defined medium. Immunocytochemistry and Western blotting for smooth muscle α‐actin filament formation, smooth muscle α‐actin protein levels, calponin expression, PCNA index, and androgen receptor localization were performed. RESULTS Dihydrotestosterone (DHT) and TGF‐β1 each separately promoted PS‐1 myodifferentiation. A combination did not affect the rate of differentiation, however, the level of α‐actin protein was elevated and PCNA was decreased in co‐stimulated conditions. TGF‐β1 induction resulted in a transient translocation of androgen receptor from the nucleus to the cytoplasm during differentiation followed by a resumed nuclear localization in myodifferentiated cells. CONCLUSIONS These data indicate that a complex cross‐talk mechanism exists between androgen and TGF‐β1 signaling in prostate stromal cells that affects cell proliferation and myodifferentiation. These findings also suggest that androgen and TGF‐β1 interactions may cooperatively regulate myodifferentiation of stromal cells in the stromal response in prostate cancer.