Exp Mol Med.
2012 Apr;44(4):281-292. 10.3858/emm.2012.44.4.024.
A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells
- Affiliations
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- 1Molecular Pathogenesis Group, National Toxicology Program (NTP) Laboratories Branch, NTP, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, Nor
- 2Microarray Group, Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina 27709, USA.
- 3Bureau of Health of Wujin District, Changzhou 213159, China.
- 4Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
- KMID: 1365905
- DOI: http://doi.org/10.3858/emm.2012.44.4.024
Abstract
- 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(TM), we identified genes (up- or down-regulated, > or = 1.5 fold, P < or = 0.001), functions and signaling pathways that were altered following treatment with an inhibitory concentration of genistein (50 microg/ml) in UtLM cells. Downregulation of TGF-beta signaling pathway genes, activin A, activin B, Smad3, TGF-beta2 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-beta 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.
Keyword
MeSH Terms
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Activins/*genetics/metabolism/pharmacology
Anticarcinogenic Agents/*pharmacology
Cell Line, Tumor
Cell Proliferation/drug effects
Cyclin-Dependent Kinase Inhibitor p15/genetics/metabolism
Down-Regulation
Female
Genistein/*pharmacology
Humans
Leiomyoma/*metabolism
Oligonucleotide Array Sequence Analysis
Signal Transduction/drug effects
Smad3 Protein/*genetics/metabolism
Transforming Growth Factor beta/*genetics/metabolism
Up-Regulation
Uterine Neoplasms/*metabolism
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