E2F activity is biphasically regulated by androgens in LNCaP cells

Androgens exert a peculiar biphasic dose-dependent influence on the prolife ration of LNCaP cells, a widely used model to study androgen effects on pro state cancer cells. Low concentrations of androgen stimulate proliferation, but high concentrations inhibit proliferation and induce strong expression of differentiation markers. In order to gain more insight into the molecul ar mechanisms that underlie these changes we studied the influence of a wid e concentration range of the synthetic androgen R1881 on several cell cycle - and differentiation-related parameters. Low concentrations (0.1 nM), know n to promote LNCaP cell proliferation, induce an increase of Retinoblastoma protein phosphorylation, accompanied by an increase of E2F-1 protein level s and E2F activity and by increased expression of the E2F-target gene produ cts E2F-1 and cyclin A. High concentrations of R1881 (10 nM) induce strong expression of the differentiation marker prostate-specific antigen. Retinob lastoma protein is largely hypophosphorylated, resulting in low E2F activit y and low concentrations of E2F-1 and cyclin A mRNA. Finally, there is a st rong increase of p27(Kip1) protein, but not of p27(Kip1) mRNA. These result s indicate that the biphasic dose response of LNCaP proliferation to androg en is closely reflected in Rb phosphorylation, E2F activity and p27(Kip1) p rotein expression. (C) 2001 Academic Press.