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J. Biol. Chem., Vol. 282, Issue 10, 7329-7338, March 9, 2007

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Insulin-like Growth Factor 1/Insulin Signaling Activates Androgen Signaling through Direct Interactions of Foxo1 with Androgen Receptor^*

WuQiang Fan, Toshihiko Yanase¹, Hidetaka Morinaga, Taijiro Okabe, Masatoshi Nomura, Hiroaki Daitoku, Akiyoshi Fukamizu, Shigeaki Kato^¶, Ryoichi Takayanagi, and Hajime Nawata^||

From the Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, ^¶Institute of Molecular and Cellular Biosciences, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo 113-0032, and ^||Graduate School of Medical Science, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan

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.

Received for publication, November 9, 2006 , and in revised form, December 15, 2006.

^* This work was supported by a grant-in-aid for the "Mechanism of Sex Differentiation" and a grant from the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–9.

¹ To whom correspondence should be addressed. Tel.: 81-92-642-5280; Fax: 81-92-642-5287; E-mail: yanase{at}intmed3.med.kyushu-u.ac.jp.

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