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Chapter 23 Modification of Androgen Receptor Function by Igf‐1 Signaling:Implications in the Mechanism of Refractory Prostate Carcinoma

Authors
Publisher
Elsevier Science & Technology
Identifiers
DOI: 10.1016/s0083-6729(08)00623-7
Keywords
  • Androgen Receptor
  • Foxo1
  • Transcriptional Repression
  • Insulin
  • Insulin‐Like Growth Factor 1
  • Prostate Cancer
Disciplines
  • Biology

Abstract

Abstract 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.

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