Modification of androgen receptor function by IGF-1 signaling implications in the mechanism of refractory prostate...

The androgen-androgen receptor (AR) system plays important roles in a variety of biological processes, including prostate cancer (PC) development and progression. Insulin and Insulin-like growth factor-1 (IGF-1) signaling negatively regulate a member of the forkhead box-containing protein O subfamily (FoxO), Foxo-1, and associated biological functions. IGF-1 can potentiate androgen signaling through AR activation. Foxo-1, phosphorylated and inactivated by phosphatidylinositol-3-kinase (PI3K)/Akt kinase induced by IGF-1 or insulin, suppresses ligand-mediated AR transactivation. Foxo-1 reduces expression of androgen-induced AR target genes and suppresses in vitro growth of PC cells. These inhibitory effects of Foxo-1 are attenuated by IGF-1, but enhanced when it was rendered Akt-non-phosphorylatable. Foxo-1 directly interacts with the C-terminus of AR in a ligand-dependent manner, and disrupts ligand-induced AR subnuclear compartmentalization. Foxo-1 is recruited by liganded AR to the chromatin of the AR target gene promoter, while IGF-1 or insulin abolishes the Foxo-1 occupancy on the promoter. Liganded AR stimulates IGF-1 receptor expression, suggesting the presence of local positive feedback between IGF-1 and AR signaling in PC cells, presumably resulting in higher IGF-1 signaling tension and further enhancing the functions of the receptor itself. Thus, Foxo-1 is a novel corepressor for AR and IGF-1/insulin signaling may confer stimulatory effects on AR by attenuating Foxo-1 inhibition. Positive feedback between the growth factor and androgen in the local cellular environment may play important roles in AR transactivation regulation in several clinical situations including refractory PC.