HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 45, 32856-32866, November 9, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/45/32856    most recent M701459200v2 M701459200v1 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 Google Scholar Google Scholar Articles by Kang, N. J. Articles by Dong, Z. Search for Related Content PubMed PubMed Citation Articles by Kang, N. J. Articles by Dong, Z. Social Bookmarking                      What's this?

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

Nam Joo Kang¹², Ki Won Lee^¶1, Evgeny A. Rogozin, Yong-Yeon Cho, Yong-Seok Heo^||, Ann M. Bode, Hyong Joo Lee³, and Zigang Dong⁴

From the Hormel Institute, University of Minnesota, Austin, Minnesota 55912, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Republic of Korea, ^¶Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea, and ^||Department of Chemistry, Konkuk University, Seoul 143-701, Republic of Korea

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.

Received for publication, February 20, 2007 , and in revised form, July 11, 2007.

^* The work is supported in part by The Hormel Foundation and National Institutes of Health Grants CA120388, CA111536, CA88961, and CA81064 and by BioGreen21 Program Grant 20070301-034-042, Rural Development Administration, Republic of Korea. 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 These authors contributed equally to this work.

² Recipient of a BK21 fellowship from the Korea Ministry of Education.

³ To whom correspondence may be addressed. Tel.: 82-2-880-4860; Fax: 82-2-873-5095; E-mail: leehyjo{at}snu.ac.kr. ⁴ To whom correspondence may be addressed: Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912. Tel.: 507-437-9600; Fax: 507-437-9606; E-mail: zgdong{at}hi.umn.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?