INSULIN-LIKE-GROWTH-FACTOR BINDING PROTEIN-3 AND PROTEIN-5 ARE REGULATED BY TRANSFORMING-GROWTH-FACTOR-BETA AND RETINOIC ACID IN THE HUMAN PROSTATE ADENOCARCINOMA CELL-LINE PC-3

The family of insulin-like growth factor binding proteins (IGFBPs) can affect cell proliferation by modulating the availability and bioactiv ity of insulin-like growth factors (IGFs), or by mechanisms independen t of IGFs. To understand better the role(s) of IGFBPs in prostate grow th and malignancy, we examined the regulation of IGFBPs in PC-3 cells, a human prostatic adenocarcinoma epithelial cell line that is androge n-insensitive. Both transforming growth factor-beta (TGF-beta) and ret inoic acid (RA), known inhibitors of cellular proliferation, significa ntly changed the IGFBP profile in PC-3 cells. In cells that were treat ed with transforming growth factor beta-2 (TGF-beta 2) (0.5-10 ng/mL), IGFBP-3, and IGFBP-5 protein and mRNA increased in a time-and dose-de pendent manner. At 10 ng/mL TGF-beta, IGFBP-3, and IGFBP-5 protein con centrations were 14- and 9-fold, respectively, over that of controls. Cells treated with RA (0-1 mu M) also showed a time-and dose-dependent increase in IGFBP-3 protein and mRNA levels. However, in contrast to TGF-beta 2, high concentrations of RA (1 mu M) negatively regulated IG FBP-5 expression, with IGFBP-5 mRNA levels downregulated to 20% of tha t of the control, and protein levels were decreased by 50%, Since both TGF-beta and RA increased IGFBP-3 expression and both are known to in hibit prostate cell growth, we speculate that the inhibition of growth is mediated, at least in part, by IGFBP-3.