MEDIATION OF GLUCOCORTICOID RECEPTOR FUNCTION BY TRANSFORMING GROWTH-FACTOR-BETA-I EXPRESSION IN HUMAN PC-3 PROSTATE-CANCER CELLS

We investigated the role of glucocorticoids in controlling the prolife ration of androgen-independent PC-3 human prostate cancer cells via th e action of transforming growth factor beta 1 (TGF beta 1). The presen ce of glucocorticoid receptor (GR) in PC-3 cells was detected by immun oblotting analysis using a rabbit anti-GR polyclonal antibody against the synthetic human GR peptide (hGR(383-393)). In PC-3 cells, GR bound radiolabeled dexamethasone with an affinity similar to wild-type GR. In addition, GR-ligand complex bound radiolabeled DNA as detected by D NA band-shift analysis on gel. electrophoresis and transactivated the mouse mammary tumor virus-thymidine kinase-chloramphenicol acetyltrans ferase chimeric gene in transiently transfected PC-3 cells. Dexamethas one (0.1 up to 100 nM) and TGF beta 1 (0.5 up to 50 ng/ml) inhibited P C-3 cell proliferation. TGF beta 1 and dexamethasone both increased th e distribution of PC-3 cells into the G(1)/G(0) phase of the cell cycl e. Platelet-derived growth factor (PDGF) stimulated the proliferation of PC-3 cells and overcame dexamethasone's inhibition of PC-3 cell gro wth. Dexamethasone's inhibition (10(-7)M) of PC-3 cell growth was comp letely neutralized by RU 486 (10(-6)M) and partly neutralized by anti- TGF beta 1 polyclonal antibody. Furthermore, dexamethasone up modulate d the expression of TGF beta 1 mRNA in PC-3 cells. Because dexamethaso ne's inhibition was neutralized at least in part by an anti-TGF beta 1 polyclonal antibody and dexamethasone up modulated the expression of TGF beta 1 mRNA in PC-3 cells, we conclude that GR function in human P C-3 prostate cancer cells is mediated at least in part by TGF beta 1 e xpression. (C) 1995 Wiley-Liss, Inc.