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J. Biol. Chem., Vol. 282, Issue 29, 21542-21550, July 20, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/29/21542    most recent M701978200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, Y. Articles by Sarkar, F. H. Search for Related Content PubMed PubMed Citation Articles by Li, Y. Articles by Sarkar, F. H. Social Bookmarking                      What's this?

Regulation of FOXO3a/-Catenin/GSK-3 Signaling by 3,3'-Diindolylmethane Contributes to Inhibition of Cell Proliferation and Induction of Apoptosis in Prostate Cancer Cells^*

Yiwei Li, Zhiwei Wang, Dejuan Kong, Shalini Murthy, Q. Ping Dou, Shijie Sheng, G. Prem Veer Reddy, and Fazlul H. Sarkar¹

From the Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201 and the Vattikuti Urology Institute, Henry Ford Hospital, Detroit, Michigan 48201

Previous studies from our laboratory have shown anti-proliferative and pro-apoptotic effects of 3,3'-diindolylmethane (DIM) through regulation of Akt and androgen receptor (AR) in prostate cancer cells. However, the mechanism by which DIM regulates Akt and AR signaling pathways has not been fully investigated. It has been known that FOXO3a and glycogen synthase kinase-3 (GSK-3), two targets of activated Akt, interact with -catenin, regulating cell proliferation and apoptotic cell death. More importantly, FOXO3a, GSK-3, and -catenin are all AR coregulators and regulate the activity of AR, mediating the development and progression of prostate cancers. Here, we investigated the molecular effects of B-DIM, a formulated DIM with higher bioavailability, on Akt/FOXO3a/GSK-3/-catenin/AR signaling in hormone-sensitive LNCaP and hormone-insensitive C4-2B prostate cancer cells. We found that B-DIM significantly inhibited the phosphorylation of Akt and FOXO3a and increased the phosphorylation of -catenin, leading to the inhibition of cell growth and induction of apoptosis. We also found that B-DIM significantly inhibited -catenin nuclear translocation. By electrophoretic mobility shift and chromatin immunoprecipitation assays, we found that B-DIM inhibited FOXO3a binding to the promoter of AR and promoted 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 prostate cancer cells. These results suggest that B-DIM-induced cell growth inhibition and apoptosis induction are partly mediated through the regulation of Akt/FOXO3a/GSK-3/-catenin/AR signaling. Therefore, B-DIM could be a promising non-toxic agent for possible treatment of hormone-sensitive but most importantly hormone-refractory prostate cancers.

Received for publication, March 7, 2007 , and in revised form, May 14, 2007.

^* This work was supported by Department of Defense Prostate Cancer Research Program Grant DAMD17-03-1-0042 (to F. H. S.), NCI, National Institutes of Health Grant 5R01CA108535 (to F. H. S.), and 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. A.

¹ To whom correspondence should be addressed: 740 Hudson Webber Cancer Research Center, 4100 John Rd., Detroit, MI 48201. Tel.: 313-576-8327; Fax: 313-576-8389; E-mail: fsarkar{at}med.wayne.edu.

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