Modification of androgen receptor function by IGF-1 signaling implications in the mechanism of refractory prostate carcinoma.
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.
Yanase
Toshihiko
T
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Fan
Wuqiang
W
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction
D000970:Antineoplastic Agents; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D011944:Receptors, Androgen; D007334:Insulin-Like Growth Factor I