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. 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. Androgen receptor (AR) 2The abbreviations used are: AR, androgen receptor; hAR, human AR; ARE, androgen-response element; ChIP, chromatin immunoprecipitation; DHT, 5α-dihydrotestosterone; ER, estrogen receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GR, glucocorticoid receptor; IGF1, insulin-like growth factor 1; IGF1R, insulin-like growth factor 1 receptor; MMTV, mouse mammary tumor virus; PC, prostate cancer; PI3K, phosphatidylinositol 3-kinase; PR, progesterone receptor; PSA, prostate-specific antigen; PTEN, human phosphatase and tensin homolog (mutated in multiple advanced cancers 1; EIA, enzyme immunoassay; PBS, phosphate-buffered saline; ANOVA, analysis of variance; HI, heterogeneity index. 2The abbreviations used are: AR, androgen receptor; hAR, human AR; ARE, androgen-response element; ChIP, chromatin immunoprecipitation; DHT, 5α-dihydrotestosterone; ER, estrogen receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GR, glucocorticoid receptor; IGF1, insulin-like growth factor 1; IGF1R, insulin-like growth factor 1 receptor; MMTV, mouse mammary tumor virus; PC, prostate cancer; PI3K, phosphatidylinositol 3-kinase; PR, progesterone receptor; PSA, prostate-specific antigen; PTEN, human phosphatase and tensin homolog (mutated in multiple advanced cancers 1; EIA, enzyme immunoassay; PBS, phosphate-buffered saline; ANOVA, analysis of variance; HI, heterogeneity index. is a member of a nuclear receptor superfamily and functions as a ligand-dependent transcription factor. The androgen-AR system mediates male sexual differentiation in the uterus, sperm production at puberty, prostate development in the adult, and primary prostate cancer (PC) growth in patients with PC (1Brinkmann A.O. Trapman J. Adv. Pharmacol. 2004; 47: 317-341Crossref Scopus (36) Google Scholar). PC is the most common malignancy in men worldwide and the second leading cause of cancer-related mortality in the United States (2Greenlee R.T. Murray T. Bolden S. Wingo P.A. CA-Cancer. J. Clin. 2000; 50: 7-33Crossref PubMed Scopus (3971) Google Scholar). The fact that over 70% of PCs rely on androgen stimulation for growth sets the basis for androgen ablation therapy, which is initially effective but invariably results in treatment resistance after a period of time (3Santos A.F. Huang H. Tindall D.J. Steroids. 2004; 69: 79-85Crossref PubMed Scopus (62) Google Scholar). The disease is then referred to as androgen-independent PC and progresses to a fatal outcome. Recent loss-of-function studies have revealed that AR still plays a key role in hormone-refractory progression of PC (4Zegarra-Moro O.L. Schmidt L.J. Huang H. Tindall D.J. Cancer Res. 2002; 62: 1008-1013PubMed Google Scholar, 5Chen C.D. Welsbie D.S. Tran C. Baek S.H. Chen R. Vessella R. Rosenfeld M.G. Sawyers C.L. Nat. Med. 2004; 10: 33-39Crossref PubMed Scopus (1960) Google Scholar). An adaptation of AR signaling in order to function under low or absent androgen levels may occur (6Buchanan G. Irvine R.A. Coetzee G.A. Tilley W.D. Cancer Metastasis Rev. 2001; 20: 207-223Crossref PubMed Scopus (145) Google Scholar). Among the various suggested mechanisms by which AR may be reactivated in a low androgen environment (7Grossmann M.E. Huang H. Tindall D.J. J. Natl. Cancer. Inst. 2001; 93: 1687-1697Crossref PubMed Scopus (468) Google Scholar), signaling by growth factors, especially insulin-like growth factor 1 (IGF1), is reportedly of significant importance (8Pollak M. Beamer W. Zhang J.C. 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Inst. 1998; 90: 911-915Crossref PubMed Scopus (515) Google Scholar), whereas IGF1 enhances AR transactivation under very low or absent androgen levels (12Culig Z. Hobisch A. Cronauer M.V. Radmayr C. Trapman J. Hittmair A. Bartsch G. Klocker H. Cancer Res. 1994; 54: 5474-5478PubMed Google Scholar, 13Orio Jr., F. Terouanne B. Georget V. Lumbroso S. Avances C. Siatka C. Sultan C. Mol. Cell. Endocrinol. 2002; 198: 105-114Crossref PubMed Scopus (53) Google Scholar) and promotes PC cell proliferation (10Burfeind P. Chernicky C.L. Rininsland F. Ilan J. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 7263-7268Crossref PubMed Scopus (227) Google Scholar). Recent studies have also revealed that high serum insulin levels are associated with an increased incidence of PC (14Amling C.L. Curr. Opin. Urol. 2005; 15: 167-171Crossref PubMed Scopus (75) Google Scholar, 15Hsing A.W. Gao Y.T. Chua Jr., S. Deng J. Stanczyk F.Z. J. Natl. Cancer Inst. 2003; 95: 67-71Crossref PubMed Scopus (176) Google Scholar), although there is a lack of mechanistic studies implicating insulin signaling in the regulation of AR function. Foxo1, also known as FKHR, together with other two homologs, FKHRL1 and AFX, belong to the Foxo subfamily of the forkhead transcription factor family, which includes a large array of transcription factors characterized by the presence of a conserved 110-amino acid winged helix DNA-binding domain (16Kops G.J. Burgering B.M. J. Mol. Med. 1999; 77: 656-665Crossref PubMed Scopus (252) Google Scholar). Foxo subfamily members play important roles in cell cycle regulation and apoptosis, as well as in metabolic homeostasis (17Nakae J. Barr V. Accili D. EMBO J. 2000; 19: 989-996Crossref PubMed Scopus (254) Google Scholar). Phosphatidylinositol 3-kinase (PI3K)/Akt signaling, which is activated by both liganded IGF1 receptor (IGF1R) and insulin receptor, phosphorylates each of the Foxo proteins at three different Ser/Thr residues (17Nakae J. Barr V. Accili D. EMBO J. 2000; 19: 989-996Crossref PubMed Scopus (254) Google Scholar). The phosphorylated Foxo proteins become inactive and are exported from the nucleus. Subsequently, they become sequestered in the cytoplasm, where they interact with 14-3-3 protein. In this study, we observe that Foxo1, which is endogenously expressed in PC cells, can interact with AR via the C terminus of the receptor in a ligand-dependent manner and suppress ligand-induced AR transactivation. Foxo1 impaired AR signaling by interfering with ligand-induced AR nuclear translocation and subnuclear compartmentalization as well as receptor-target gene promoter interactions. Furthermore, IGF1/insulin-PI3K/Akt pathway-induced phosphorylation of Foxo1 ameliorated the suppression. liganded AR the presence of positive feedback IGF1 and AR signaling in PC cells. human PC cell and as G. M. H. T. T. H. J. H. J. 2005; PubMed Scopus Google Scholar). and in with and in in a at The IGF1 insulin and The and as well as expression for human AR estrogen receptor and and an and expression for and and G. M. H. T. T. H. J. H. J. 2005; PubMed Scopus Google Scholar, A. H. M. T. T. R. H. J. 2001; PubMed Scopus Google Scholar, M. R. A. A. T. H. Mol. Endocrinol. 2002; PubMed Scopus Google Scholar, J. H. A. W. J. Clin. Google Scholar). and to and expression from human phosphatase and tensin homolog (mutated in multiple advanced cancers from the to a for and G. M. H. T. T. H. J. H. J. 2005; PubMed Scopus Google Scholar). and as W. T. H. M. M. T. J. S. R. H. Mol. Endocrinol. 2004; PubMed Scopus Google Scholar). or of or proliferation of or the a cell proliferation to the and and as H. H. R. Mol. Cell. PubMed Scopus Google Scholar). cell as W. T. H. M. M. T. J. S. R. H. Mol. Endocrinol. 2004; PubMed Scopus Google Scholar). and the as W. T. H. M. T. H. 2005; PubMed Scopus Google Scholar). An and is in by time a as W. T. M. T. T. H. S. H. 2005; 54: PubMed Scopus Google Scholar, Res. 2001; PubMed Scopus Google Scholar). for each target is of human the cell an enzyme at expressed as and by or ANOVA, by with significant of Foxo1 AR and the effects of Foxo1 on the transactivation by AR with and an for AR together with of a Foxo1 expression in Foxo1 transcription from the promoter in a the transactivation of AR by the promoter in human PC by Foxo1 in a manner Foxo1 also liganded expression of the promoter of a AR target PSA, in both and human PC cells. Thus, the inhibitory of Foxo1 on AR, or is to cell Foxo1 by in PC cell and cells, with and higher expression levels and further the of the inhibitory effects of Foxo1 on AR in the promoter the expression levels in or the in and which in of both the by time and the of the by in Foxo1, that Foxo1 the expressions of as an for Foxo1 in cells, and results Foxo1 also on other it enhanced the transcription by liganded and on but function in a manner to that for Thus, the inhibitory effects are for AR and are PC cells, and proliferation is on the of androgen as well as the effects of Foxo1 on cell the two cell or the in serum with or and a time Among the in the presence of DHT, the of with cells, after 1 of and then to in a manner The proliferation in the presence of also to in the cells, but in with Thus, Foxo1 the proliferation of cells. IGF1 Foxo1 over AR Foxo1 is a target of kinase and by phosphorylation in an with nuclear and IGF1 or insulin is to the inhibitory effects of Foxo1 on we that a with three target residues to and Foxo1 at AR transactivation in cells, in which the impaired signaling by of lack PTEN, and is A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, M.E. P. S. M. Cancer Res. 1999; Google In these cells, IGF1 liganded promoter Of the AR transactivation by but by In other IGF1 the of liganded AR by Foxo1 but that by the Foxo1 The by IGF1 and also in cells, which and signaling insulin, also enhanced the AR transactivation in the in a the that Foxo1 AR transactivation by the of the receptor, the AR by under the used for the in of Foxo1 with AR the AR in the presence or of the AR expression in these that Foxo1 suppresses the of the Foxo1 and we there is a AR and Foxo1 by with and together with and in with IGF1, insulin, or in with or in in from with whereas a very in that Foxo1 and AR interact and is enhanced by the AR The presence of IGF1 or insulin abolish the and although both to the of Foxo1 with liganded In Foxo1 in from with or the of the cells, we further that AR and Foxo1 in an manner that the is and that Foxo1 may liganded activated AR via a The further by G. Chen Zhang A. A. F. J.C. H. Chen J. 2003; PubMed Scopus Google Scholar). with an and AR together with Foxo1, or and then with or two and in AR transactivation as a domain to the Foxo1 enhanced the liganded AR and the of and the Thus, although Foxo1 AR, an for AR, and this that there is a AR and the and the that an can induce the of the of AR for the with Foxo1 by in which the AR terminus and C terminus to the DNA-binding domain of to and a the Foxo1 to the domain in the or In with the of the with in the presence or of the a lack of the AR terminus and Foxo1 In the of but the in the presence of These that the AR C terminus interacts with Foxo1 in a Foxo1 and AR in of in with (17Nakae J. Barr V. Accili D. EMBO J. 2000; 19: 989-996Crossref PubMed Scopus (254) Google Scholar), in in the in a with also in the the nuclear of Foxo1 the presumably because of IGF1/insulin signaling the different cells, because with IGF1 of the to in the with very nuclear in the of the whereas nuclear translocation and subnuclear and both proteins in with the Among the with the of whereas nuclear translocation and impaired subnuclear compartmentalization and in both the and a of nuclear impaired In with IGF1 exported to the cytoplasm, whereas with nuclear In with in with both nuclear translocation also subnuclear compartmentalization. the effects of on the subnuclear of liganded AR, the of in the cell in and to the as W. T. H. M. M. T. J. S. R. H. Mol. Endocrinol. 2004; PubMed Scopus Google Scholar). In and the of and In from each to the The of the in whereas of Foxo1 in the to that the AR in these The value to in further with IGF1 in that the subnuclear of liganded AR by a high of AR, which subnuclear and in the presence of H. H. R. Mol. Cell. PubMed Scopus Google Scholar). Foxo1 also suppresses the of AR, expressed in cells, and the AR in the presence and of by in AR by Foxo1 the of liganded nuclear AR in the of Foxo1 but to by The of in and with both in that a of Foxo1 in the and is in to that in the in and where IGF1 nuclear of Foxo1 in cells. These suggest that liganded AR sequestered of the Foxo1 in the in the presence of Furthermore, the nuclear Foxo1 in these and with AR and an the two In to in the in a manner of the IGF1 Furthermore, it AR and the by IGF1 of Foxo1 and AR the to Foxo1 and AR with the chromatin of an AR target gene promoter in with and to serum and with IGF1, insulin, or as a in the presence of or the to the androgen-response and which are in the promoter and of the in a as an in the of whereas treatment of the with IGF1 or insulin or the occupancy of the by Foxo1, of the presence or of very Foxo1 occupancy of the in a the and the but in the presence of DHT, the in the presence of IGF1 or The of Foxo1 with the promoter because from the gene Thus, AR of Foxo1 with chromatin on the that Foxo1 and AR a ligand-dependent on Furthermore, IGF1 and insulin are to Foxo1 from The further revealed that Foxo1 with ligand-induced of AR to the promoter in cells. The with together with or and with the as factor with an and with time analysis to the of to the for each as W. T. H. M. T. H. 2005; PubMed Scopus Google Scholar). of the to and in the of DHT, and significant of these IGF1 or insulin increased the AR-DNA under each or of of the the of promoter at both especially in the presence of that the the promoter and liganded AR Furthermore, also the to IGF1 and insulin that and Foxo1 is vital for IGF1 or insulin to the liganded AR-DNA of AR in further that expression in in the presence of in treatment for increased the levels in cells, and the by stimulation of because of the levels of growth factor receptor and Foxo1 An may because the is to signaling, resulting in a further of AR via phosphorylation of the Foxo1 and of is of AR in low or absent androgen and of the suggested multiple mechanisms by which PC to the (7Grossmann M.E. Huang H. Tindall D.J. J. Natl. Cancer. 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AR also recruited Foxo1 to the chromatin of AR target gene promoters, where Foxo1, in with AR-DNA of AR subnuclear compartmentalization. IGF1 or insulin, the occupancy by Foxo1 but enhanced that by These IGF1/insulin rely on phosphorylation of Foxo1, because the AR-DNA as well as the AR by Thus, IGF1, and also insulin, to the via phosphorylation of is important to that the effects of IGF1 and insulin on AR function are but IGF1 is and at enhancing AR the and the AR subnuclear compartmentalization although the that in the is presumably because of phosphorylation of Foxo1 in response to IGF1 and insulin both to and the kinase which phosphorylates Foxo1 at and studies on (17Nakae J. Barr V. Accili D. 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These in with suggest that AR and Foxo1 are in of the of Foxo1 an in which liganded AR may the The Foxo1 and AR in the of IGF1 signaling may play an important role in AR function and prostate cell apoptosis, as well as in PC and progression the results have Foxo1, a molecule by signaling, as a novel corepressor for The results further suggest that positive feedback the growth factor and androgen in the environment may play important roles in the regulation of AR transactivation. These a by which IGF1, and also insulin, enhances AR transactivation and may on of the progression of PC to the that IGF1/insulin signaling, in with are to have clinical in with