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

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 c...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-07, Vol.282 (27), p.19385-19398
Main Authors: Su, Jen-Liang, Yang, Ching-Yao, Zhao, Ming, Kuo, Min-Liang, Yen, Men-Luh
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents, Phytogenic - pharmacology
Antineoplastic Agents, Phytogenic - therapeutic use
Bone Morphogenetic Protein 2
Bone Morphogenetic Proteins - biosynthesis
Breast Neoplasms - metabolism
Cell Line, Tumor
Estrogen Replacement Therapy
Estrogens - pharmacology
Estrogens - therapeutic use
Female
Forkhead Transcription Factors - metabolism
Gene Expression Regulation, Enzymologic - drug effects
Humans
Mice
Osteoporosis, Postmenopausal - drug therapy
Osteoporosis, Postmenopausal - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Receptors, Estrogen - agonists
Receptors, Estrogen - metabolism
Resveratrol
Risk Factors
src-Family Kinases - metabolism
Stilbenes - pharmacology
Stilbenes - therapeutic use
Transforming Growth Factor beta - biosynthesis
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M702452200