Equol, a Metabolite of the Soybean Isoflavone Daidzein, Inhibits Neoplastic Cell Transformation by Targeting the MEK/ERK/p90RSK/Activator Protein-1 Pathway
Open accessAbstract
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.
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The blocked AP-1 actions by equol may be mediated by a common mechanism involving ER β signaling.
“Finally, ER β signaling has been shown to protect against transplanted skin tumor growth in mice, which implicated a common mechanism of how the blocked AP-1 actions by equol reported by Kang et al. may be mediated [101,102].”
ER β signaling protects against transplanted skin tumor growth in mice.
“Finally, ER β signaling has been shown to protect against transplanted skin tumor growth in mice, which implicated a common mechanism of how the blocked AP-1 actions by equol reported by Kang et al. may be mediated [101,102].”
Kang et al. (2007) reported that the anti-tumor effects of equol are due to the inhibition of cell transformation by the MEK signaling pathway by blocking AP-1.
“Kang et al., in 2007, reported that the anti-tumor effects of equol are due to the inhibition of cell transformation by the MEK signaling pathway by blocking AP-1 [101].”
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- Authors
- Kang, N. J., Lee, K. W., Rogozin, E. A., Cho, Y.-Y., Heo, Y.-S., Bode, A. M., Lee, H. J., & Dong, Z.
- Affiliations
- University of Minnesota (US)
- Konkuk University (KR)
- Seoul National University (KR)
- Corresponding author
- Lee, Hyong Joo
- Dong, Zigang
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-11
- Volume
- 282
- Issue
- 45
- Pages
- 32856-32866
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2042596920
- Cited by
- 71
- References
- 48
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 3 · 2022: 1 · 2021: 5 · 2020: 4 · 2018: 2 · 2017: 2 · 2016: 2 · 2015: 5 · 2014: 4 · 2013: 8 · 2012: 5
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Hormel Foundation (CA111536, CA81064)
- Rural Development Administration
- National Institutes of Health (CA88961, CA81064)
- National Cancer Institute (CA 120388, R01CA111536, R01CA120388, P01CA088961, CA-81064, CA 88961, CA111536)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Phytoestrogen effects and research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioactive natural compounds
- Keywords
- equol, daidzein, soy isoflavones, MEK/ERK signaling, p90RSK, activator protein-1, Elk-1, chemoprevention, c-fos, oncogenic Ras, epidermal growth factor, H-Ras, anticarcinogenic activity
- MeSH terms
- Animals, Binding Sites, Cell Line, Epidermal Growth Factor, Isoflavones, Models, Molecular, Neoplasms, Phosphorylation, Glycine max, Tetradecanoylphorbol Acetate, Molecular Structure, Proto-Oncogene Proteins c-fos, ras Proteins, MAP Kinase Signaling System, Ribosomal Protein S6 Kinases, 90-kDa, JNK Mitogen-Activated Protein Kinases, Extracellular Signal-Regulated MAP Kinases, MAP Kinase Kinase 1, Mice, Replication Protein C, Equol
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