Equol, a Metabolite of the Soybean Isoflavone Daidzein, Inhibits Neoplastic Cell Transformation by Targeting the MEK/ERK/p90RSK/Activator Protein-1 Pathway

Daidzein and genistein are isoflavones found in soybean. Genistein is known to exhibit anticarcinogenic activities and inhibit tyrosine kinase activity. However, the underlying molecular mechanisms of the chemopreventive activities of daidzein and its metabolite, equol, are not understood. Here we r...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-11, Vol.282 (45), p.32856-32866
Main Authors: Kang, Nam Joo, Lee, Ki Won, Rogozin, Evgeny A., Cho, Yong-Yeon, Heo, Yong-Seok, Bode, Ann M., Lee, Hyong Joo, Dong, Zigang
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Cell Line
Epidermal Growth Factor - pharmacology
Equol
Extracellular Signal-Regulated MAP Kinases - metabolism
Glycine max - chemistry
Isoflavones - chemistry
Isoflavones - metabolism
Isoflavones - pharmacology
JNK Mitogen-Activated Protein Kinases - metabolism
MAP Kinase Kinase 1 - chemistry
MAP Kinase Kinase 1 - metabolism
MAP Kinase Signaling System - drug effects
Mice
Models, Molecular
Molecular Structure
Neoplasms - metabolism
Neoplasms - pathology
Phosphorylation
Proto-Oncogene Proteins c-fos - metabolism
ras Proteins - metabolism
Replication Protein C - metabolism
Ribosomal Protein S6 Kinases, 90-kDa - metabolism
Tetradecanoylphorbol Acetate - pharmacology
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Summary:Daidzein and genistein are isoflavones found in soybean. Genistein is known to exhibit anticarcinogenic activities and inhibit tyrosine kinase activity. However, the underlying molecular mechanisms of the chemopreventive activities of daidzein and its metabolite, equol, are not understood. Here we report that equol inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ mouse epidermal cells by targeting the MEK/ERK/p90RSK/activator protein-1 signaling pathway. TPA-induced neoplastic cell transformation was inhibited by equol, but not daidzein, at noncytotoxic concentrations in a dose-dependent manner. Equol dose-dependently attenuated TPA-induced activation of activator protein-1 and c-fos, whereas daidzein did not exert any effect when tested at the same concentrations. The TPA-induced phosphorylation of ERK1/2, p90RSK, and Elk, but not MEK or c-Jun N-terminal kinase, was inhibited by equol but not by daidzein. In vitro kinase assays revealed that equol greatly inhibited MEK1, but not Raf1, kinase activity, and an ex vivo kinase assay also demonstrated that equol suppressed TPA-induced MEK1 kinase activity in JB6 P+ cell lysates. Equol dose-dependently inhibited neoplastic transformation of JB6 P+ cells induced by epidermal growth factor or H-Ras. Both in vitro and ex vivo pull-down assays revealed that equol directly bound with glutathione S-transferase-MEK1 to inhibit MEK1 activity without competing with ATP. These results suggested that the antitumor-promoting effect of equol is due to the inhibition of cell transformation mainly by targeting a MEK signaling pathway. These findings are the first to reveal a molecular basis for the anticancer action of equol and may partially account for the reported chemopreventive effects of soybean.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M701459200