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J. Biol. Chem., Vol. 282, Issue 27, 19385-19398, July 6, 2007

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Forkhead Proteins Are Critical for Bone Morphogenetic Protein-2 Regulation and Anti-tumor Activity of Resveratrol^*

Jen-Liang Su^¶1, Ching-Yao Yang^||**1, Ming Zhao, Min-Liang Kuo, and Men-Luh Yen^¶¶||||2

From the Graduate Institute of Cancer Biology, College of Medicine, China Medical University, Taichung 404, Taiwan, the Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan, the ^¶Department of Biotechnology and Bioinformatics, Asia University, Taichung 41354, Taiwan, the ^||Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan, the ^**Department of Traumatology, National Taiwan University Hospital, Taipei 100, Taiwan, the Vanderbilt Center for Bone Biology, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232-0575, the Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan, the ^¶¶Department of Primary Care Medicine, National Taiwan University Hospital, College of Medicine, No. 7, Chung Shan S. Rd., Taipei 100, Taiwan, and the ^||||Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei 100, Taiwan

Osteoporosis is a major public health problem and the most obvious preventive strategy, hormone replacement therapy, has lost favor due to recent findings of the Women's Health Initiative regarding increased risks of breast cancer and cardiovascular disease. Resveratrol, a naturally occurring compound possessing estrogenic activity, is thought to have considerable potential for therapy of osteoporosis. In the present study, resveratrol was found to exhibit bone-protective effects equivalent to those exerted by hormone replacement therapy and decrease the risk of breast cancer in the in vivo and in vitro models. Forkhead proteins were found to be essential for both effects of resveratrol. The bone-protective effect was attributable to induction of bone morphogenetic protein-2 through Src kinase-dependent estrogen receptor activation and FOXA1 is required for resveratrol-induced estrogen receptor-dependent bone morphogenetic protein-2 expression. The tumor-suppressive effects of resveratrol were the consequence of Akt inactivation-mediated FOXO3a nuclear accumulation and activation. Resveratrol is therefore anticipated to be highly effective in management of postmenopausal osteoporosis without an increased risk of breast cancer.

Received for publication, March 22, 2007 , and in revised form, May 14, 2007.

^* This work was supported by National Science Council, Taiwan (Grants NSC 94-2314-B-002-212, NSC 95-2314-B-002-281, NSC 95-2314-B-002-110-MY3, and NSC 96-2320-B-039-004-MY2) and by the Ministry of Economic Affairs, Taipei, Taiwan (Grant 93-EC-17-A-19-S1-0016). The luciferase expression plasmids under the control of the BMP-2 promoter (pBMP-2-Luc) were kindly provided by G. R. Mundy (Medicine, Pharmacology, Orthopedics, Cancer Biology, Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center). The authors have declared that no conflict of interest exists. 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. S1 and S2 and Table S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed (present address): Dept. of Primary Care Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, No. 7, Chung Shan S. Rd., Taipei, Taiwan. Tel.: 886-2-23123456 (ext. 5122); Fax: 886-2-2391-1302; E-mail: ntu88447004.tw{at}yahoo.com.tw.

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