title: Insulin-like growth factor 1/insulin signaling activates androgen signaling through direct interactions of Foxo1 with androgen receptor.
abstract: The androgen-androgen receptor (AR) system plays vital roles in a wide array of biological processes, including prostate cancer development and progression. Several growth factors, such as insulin-like growth factor 1 (IGF1), can induce AR activation, whereas insulin resistance and hyperinsulinemia are correlated with an elevated incidence of prostate cancer. Here we report that Foxo1, a downstream molecule that becomes phosphorylated and inactivated by phosphatidylinositol 3-kinase/Akt kinase in response to IGF1 or insulin, suppresses ligand-mediated AR transactivation. Foxo1 reduces androgen-induced AR target gene expressions and suppresses the in vitro growth of prostate cancer cells. These inhibitory effects of Foxo1 are attenuated by IGF1 but are enhanced when it is rendered Akt-nonphosphorylatable. Foxo1 interacts directly with the C terminus of AR in a ligand-dependent manner and disrupts ligand-induced AR subnuclear compartmentalization. Foxo1 is recruited by liganded AR to the chromatin of AR target gene promoters, where it interferes with AR-DNA interactions. IGF1 or insulin abolish the Foxo1 occupancy of these promoters. Of interest, a positive feedback circuit working locally in an autocrine/intracrine manner may exist, because liganded AR up-regulates IGF1 receptor expression in prostate cancer cells, presumably resulting in higher IGF1 signaling tension and further enhancing the functions of the receptor itself. Thus, Foxo1 is a novel corepressor for AR, and IGF1/insulin signaling may confer stimulatory effects on AR by attenuating Foxo1 inhibition. These results highlight the potential involvement of metabolic syndrome and hyperinsulinemia in prostate diseases and further suggest that intervention of IGF1/insulin-phosphatidylinositol 3-kinase-Akt signaling may be of clinical value for prostate diseases.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582.
authors.forename: WuQiang
authors.initials: W
authors.lastname: Fan
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yanase
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Morinaga
authors.forename: Taijiro
authors.initials: T
authors.lastname: Okabe
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nomura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Daitoku
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
authors.forename: Hajime
authors.initials: H
authors.lastname: Nawata
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D013196:Dihydrotestosterone / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008297:Male; D051059:PTEN Phosphohydrolase / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics*; D012097:Repressor Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: D013196:Dihydrotestosterone; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017430:Prostate-Specific Antigen; D011944:Receptors, Androgen; D012097:Repressor Proteins; C085126:FOXO1 protein, human; C494929:PTEN protein, human