7,3',4'-trihydroxyisoflavone, a metabolite of the soy isoflavone Daidzein, suppresses ultraviolet B-induced skin cancer by targeting Cot and MKK4

Dong Eun Lee, Ki Won Lee, Sanguine Byun, Sung Keun Jung, Nury Song, Sung Hwan Lim, Yong Seok Heo, Jong Eun Kim, Nam Joo Kang, Bo Yeon Kim, G. Tim Bowden, Ann M. Bode, Hyong Joo Lee, Zigang Dong

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Abstract

Nonmelanoma skin cancer is one of the most frequently occurring cancers in the United States. Chronic exposure to UVB irradiation is a major cause of this cancer. Daidzein, along with genistein, is a major isoflavone found in soybeans; however, little is known about the chemopreventive effects of daidzein and its metabolites in UVB-induced skin cancer. Here, we found that 7,3',4'- trihydroxyisoflavone (THIF), a major metabolite of daidzein, effectively inhibits UVB-induced cyclooxygenase 2 (COX-2) expression through the inhibition of NF-kB transcription activity in mouse skin epidermal JB6 P+ cells. In contrast, daidzein had no effect on COX-2 expression levels. Data from Western blot and kinase assays showed that 7,3',4'-THIF inhibited Cot and MKK4 activity, thereby suppressing UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays indicated that 7,3',4'-THIF competed with ATP to inhibit Cot or MKK4 activity. Topical application of 7,3',4'-THIF clearly suppressed the incidence and multiplicity of UVB-induced tumors in hairless mouse skin. Hairless mouse skin results also showed that 7,3',4'-THIF inhibits Cot or MKK4 kinase activity directly, resulting in suppressed UVB-induced COX-2 expression. A docking study revealed that 7,3',4'-THIF, but not daidzein, easily docked to the ATP binding site of Cot and MKK4, which is located between the N-and C-lobes of the kinase domain. Collectively, these results provide insight into the biological actions of 7,3',4'-THIF, a potential skin cancer chemopreventive agent.

Original languageEnglish
Pages (from-to)14246-14256
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number16
DOIs
Publication statusPublished - 2011 Apr 22

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Lee, D. E., Lee, K. W., Byun, S., Jung, S. K., Song, N., Lim, S. H., Heo, Y. S., Kim, J. E., Kang, N. J., Kim, B. Y., Bowden, G. T., Bode, A. M., Lee, H. J., & Dong, Z. (2011). 7,3',4'-trihydroxyisoflavone, a metabolite of the soy isoflavone Daidzein, suppresses ultraviolet B-induced skin cancer by targeting Cot and MKK4. Journal of Biological Chemistry, 286(16), 14246-14256. https://doi.org/10.1074/jbc.M110.147348