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J. Biol. Chem., Vol. 283, Issue 41, 27707-27716, October 10, 2008

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Regulation of Akt/FOXO3a/GSK-3β/AR Signaling Network by Isoflavone in Prostate Cancer Cells^*

From the Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201

We have previously shown that genistein could inhibit Akt activation and down-regulate AR (androgen receptor) and PSA (prostate-specific antigen) expression in prostate cancer (PCa) cells. However, pure genistein showed increased lymph node metastasis in an animal model, but such an adverse effect was not seen with isoflavone, suggesting that further mechanistic studies are needed for elucidating the role of isoflavone in PCa. It is known that FOXO3a and GSK-3β, targets of Akt, regulate cell proliferation and apoptosis. Moreover, FOXO3a, GSK-3β, and Src are AR regulators and regulate transactivation of AR, mediating the development and progression of PCa. Therefore, we investigated the molecular effects of isoflavone on the Akt/FOXO3a/GSK-3β/AR signaling network in hormone-sensitive LNCaP and hormone-insensitive C4-2B PCa cells. We found that isoflavone inhibited the phosphorylation of Akt and FOXO3a, regulated the phosphorylation of Src, and increased the expression of GSK-3β, leading to the down-regulation of AR and its target gene PSA. We also found that isoflavone inhibited AR nuclear translocation and promoted FOXO3a translocation to the nucleus. By electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we found that isoflavone inhibited FOXO3a binding to the promoter of AR and increased FOXO3a binding to the p27^KIP1 promoter, resulting in the alteration of AR and p27^KIP1 expression, the inhibition of cell proliferation, and the induction of apoptosis in both androgen-sensitive and -insensitive PCa cells. These results suggest that isoflavone-induced inhibition of cell proliferation and induction of apoptosis are partly mediated through the regulation of the Akt/FOXO3a/GSK-3β/AR signaling network. In conclusion, our data suggest that isoflavone could be useful for the prevention and/or treatment of PCa.

Received for publication, April 9, 2008 , and in revised form, June 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health, NCI, Grants 5R01CA083695 and 5R01CA101870 (to F. H. S.). This work was also supported by the Puschelberg Foundation. 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.

¹ To whom correspondence should be addressed: Dept. of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, 4100 John R, Detroit, Michigan 48201. Tel.: 313-576-8327; Fax: 313-576-8389; E-mail: fsarkar{at}med.wayne.edu.

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