Solar UV (sUV) is an important environmental carcinogen. Recent studies have shown that sUV is associated with numerous human skin disorders, such as wrinkle formation and inflammation. In this study, we found that the isoflavone, biochanin A, inhibited the expression of sUV-induced COX-2, which is a well-characterized sUV-induced enzyme, in both human HaCaT keratinocytes and JB6 P+ mouse skin epidermal cells. Several studies have demonstrated the beneficial effects of biochanin A. However, its direct molecular target is unknown. We found that biochanin A inhibited sUV-induced phosphorylation of MKK4/JNK/c-Jun and MKK3/6/p38/MSK1. Mixed-lineage kinase 3 (MLK3) is an upstream kinase of MKK4 and MKK3/6. Thus, we evaluated the effect of biochanin A on MLK3. We found that sUV-induced MLK3 phosphorylation was not affected, whereas MLK3 kinase activity was significantly suppressed by biochanin A. Furthermore, direct binding of biochanin A in the MLK3 ATP-binding pocket was detected using pull-down assays. Computer modeling supported our observation that MLK3 is a novel target of biochanin A. These results suggest that biochanin A exerts chemopreventive effects by suppressing sUV-induced COX-2 expression mediated through MLK3 inhibition.
Bibliographical noteFunding Information:
This work was supported by The Hormel Foundation and National Institutes of Health grants CA166011 , CA172457 , CA120388 , R37 CA081064 and NIESH grant ES 016548 ; the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (No. 2010-0029233 ), Interrelated Development Program (R-0000451) of Inter-Economic Regions, Ministry for Knowledge Economy and High Value-added Food Technology Development Program (311035-3), Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea .
Copyright 2014 Elsevier B.V., All rights reserved.
- Biochanin A
- Mixed-lineage kinase 3
- Solar UV