Posted by Chantel M. Contributed by US National Library of Medicine National Institutes of Health
In the study to assess the chemopreventive effects of daidzein
and its metabolites in UVB-induced skin cancer, posted in US National Library of Medicine National Institutes of Health, indicated 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-κB 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.
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