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KMID : 0620920120440040281
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Experimental & Molecular Medicine
2012 Volume.44 No. 4 p.281 ~ p.292
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A high concentration of genistein down-regulates activin A, Smad3 and other TGF-β pathway genes in human uterine leiomyoma cells
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Di Xu-Dong
Danica MK Andrews
Charles J Tucker
Yu Lin-Da
Alicia B Moore
Zheng Xiao-Lin
Lysandra Castro
Tonia Hermon
Hang Xiao
Darlene Dixon
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Abstract
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Previously, we found that high doses of genistein show an inhibitory effect on uterine leiomyoma (UtLM) cell proliferation. In this study, using microarray analysis and Ingenuity Pathways Analysis™, we identified genes (up- or down-regulated, ≥ 1.5 fold, P ≤ 0.001), functions and signaling pathways that were altered following treatment with an inhibitory concentration of genistein (50 μg/ml) in UtLM cells. Downregulation of TGF-β signaling pathway genes, activin A, activin B, Smad3, TGF-β2 and genes related to cell cycle regulation, with the exception of the upregulation of the CDK inhibitor P15, were identified and validated by real-time RT-PCR studies. Western blot analysis further demonstrated decreased protein expression of activin A and Smad3 in genistein-treated UtLM cells. Moreover, we found that activin A stimulated the growth of UtLM cells, and the inhibitory effect of genistein was partially abrogated in the presence of activin A. Overexpression of activin A and Smad3 were found in tissue samples of leiomyoma compared to matched myometrium, supporting the contribution of activin A and Smad3 in promoting the growth of UtLM cells. Taken together, these results suggest that down-regulation of activin A and Smad3, both members of the TGF-β pathway, may offer a mechanistic explanation for the inhibitory effect of a high-dose of genistein on UtLM cells, and might be potential therapeutic targets for treatment of clinical cases of uterine leiomyomas.
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KEYWORD
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activin A, genistein, leiomyoma, myometrium, oligonucleotide array sequence analysis, Smad3 protein, transforming growth factor β
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