6,7,4′-Trihydroxyisoflavone inhibits HCT-116 human colon cancer cell proliferation by targeting CDK1 and CDK2

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Title
6,7,4′-Trihydroxyisoflavone inhibits HCT-116 human colon cancer cell proliferation by targeting CDK1 and CDK2
Author(s)
D E Lee; K W Lee; S K Jung; E J Lee; J A Hwang; T G Lim; Bo Yeon Kim; A M Bode; H J Lee; Z Dong
Bibliographic Citation
Carcinogenesis, vol. 32, no. 4, pp. 629-635
Publication Year
2011
Abstract
Colon cancer is a common epithelial malignancies worldwide. Epidemiologic evidence has shown that nutrition and dietary components are important environmental factors involved in the development of this disease. We investigated the biological activity of 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF, a metabolite of daidzein) in in vitro and in vivo models of human colon cancer. 6,7,4'-THIF suppressed anchorage-dependent and -independent growth of HCT-116 and DLD1 human colon cancer cells more effectively than daidzein. In addition, 6,7,4'-THIF induced cell cycle arrest at the S and G2/M phases in HCT-116 human colon cancer cells. Western blot analysis revealed that 6,7,4'-THIF effectively suppressed the expression of cyclin-dependent kinase (CDK) 2, but had no effect on other S- or G2/M-phase regulatory proteins such as cyclin A, cyclin B1 or CDK1. Daidzein did not affect the expression of any of these proteins. In kinase and pull-down assays, 6,7,4'-THIF, but not daidzein, inhibited CDK1 and CDK2 activities in HCT-116 cells by directly interacting with CDK1 and CDK2. In a xenograft mouse model, 6,7,4'-THIF significantly decreased tumor growth, volume and weight of HCT-116 xenografts. 6,7,4'-THIF bound directly to CDK1 and CDK2 in vivo, resulting in the suppression of CDK1 and CDK2 activity in tumors corresponding with our in vitro results. Collectively, these results suggest that CDK1 and CDK2 are potential molecular targets of 6,7,4'-THIF to suppress HCT-116 cell proliferation in vitro and in vivo. These findings provide insight into the biological actions of 6,7,4'-THIF and might establish a molecular basis for the development of new cancer therapeutic agents.
ISSN
0143-3334
Publisher
Oxford Univ Press
DOI
http://dx.doi.org/10.1093/carcin/bgr008
Type
Article
Appears in Collections:
Ochang Branch Institute > Chemical Biology Research Center > 1. Journal Articles
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