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Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells

Genistein is a soy isoflavone with phytoestrogen and tyrosine kinase inhibitory properties. High intake of soy/genistein has been associated with reduced breast cancer risk. Despite the advances in genistein-mediated antitumor studies, the underlying mechanisms remain unclear. In the present study,...

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Autores principales: Zhao, Qingxia, Zhao, Ming, Parris, Amanda B., Xing, Ying, Yang, Xiaohe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948957/
https://www.ncbi.nlm.nih.gov/pubmed/27574003
http://dx.doi.org/10.3892/ijo.2016.3588
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author Zhao, Qingxia
Zhao, Ming
Parris, Amanda B.
Xing, Ying
Yang, Xiaohe
author_facet Zhao, Qingxia
Zhao, Ming
Parris, Amanda B.
Xing, Ying
Yang, Xiaohe
author_sort Zhao, Qingxia
collection PubMed
description Genistein is a soy isoflavone with phytoestrogen and tyrosine kinase inhibitory properties. High intake of soy/genistein has been associated with reduced breast cancer risk. Despite the advances in genistein-mediated antitumor studies, the underlying mechanisms remain unclear. In the present study, we investigated genistein-induced regulation of the cancerous inhibitor of protein phosphatase 2A (CIP2A), a novel oncogene frequently overexpressed in breast cancer, and its functional impact on genistein-induced growth inhibition and apoptosis. We demonstrated that genistein induced downregulation of CIP2A in MCF-7-C3 and T47D breast cancer cells, which was correlated with its growth inhibition and apoptotic activities. Overexpression of CIP2A attenuated, whereas CIP2A knockdown sensitized, genistein-induced growth inhibition and apoptosis. We further showed that genistein-induced downregulation of CIP2A involved both transcriptional suppression and proteasomal degradation. In particular, genistein at higher concentrations induced concurrent downregulation of E2F1 and CIP2A. Overexpression of E2F1 attenuated genistein-induced downregulation of CIP2A mRNA, indicating the role of E2F1 in genistein-induced transcriptional suppression of CIP2A. Taken together, our results identified CIP2A as a functional target of genistein and demonstrated that modulation of E2F1-mediated transcriptional regulation of CIP2A contributes to its downregulation. These data advance our understanding of genistein-induced growth inhibition and apoptosis, and support further investigation on CIP2A as a therapeutic target of relevant anticancer agents.
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spelling pubmed-49489572016-07-21 Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells Zhao, Qingxia Zhao, Ming Parris, Amanda B. Xing, Ying Yang, Xiaohe Int J Oncol Articles Genistein is a soy isoflavone with phytoestrogen and tyrosine kinase inhibitory properties. High intake of soy/genistein has been associated with reduced breast cancer risk. Despite the advances in genistein-mediated antitumor studies, the underlying mechanisms remain unclear. In the present study, we investigated genistein-induced regulation of the cancerous inhibitor of protein phosphatase 2A (CIP2A), a novel oncogene frequently overexpressed in breast cancer, and its functional impact on genistein-induced growth inhibition and apoptosis. We demonstrated that genistein induced downregulation of CIP2A in MCF-7-C3 and T47D breast cancer cells, which was correlated with its growth inhibition and apoptotic activities. Overexpression of CIP2A attenuated, whereas CIP2A knockdown sensitized, genistein-induced growth inhibition and apoptosis. We further showed that genistein-induced downregulation of CIP2A involved both transcriptional suppression and proteasomal degradation. In particular, genistein at higher concentrations induced concurrent downregulation of E2F1 and CIP2A. Overexpression of E2F1 attenuated genistein-induced downregulation of CIP2A mRNA, indicating the role of E2F1 in genistein-induced transcriptional suppression of CIP2A. Taken together, our results identified CIP2A as a functional target of genistein and demonstrated that modulation of E2F1-mediated transcriptional regulation of CIP2A contributes to its downregulation. These data advance our understanding of genistein-induced growth inhibition and apoptosis, and support further investigation on CIP2A as a therapeutic target of relevant anticancer agents. D.A. Spandidos 2016-06-30 /pmc/articles/PMC4948957/ /pubmed/27574003 http://dx.doi.org/10.3892/ijo.2016.3588 Text en Copyright © 2016, Spandidos Publications
spellingShingle Articles
Zhao, Qingxia
Zhao, Ming
Parris, Amanda B.
Xing, Ying
Yang, Xiaohe
Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells
title Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells
title_full Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells
title_fullStr Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells
title_full_unstemmed Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells
title_short Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells
title_sort genistein targets the cancerous inhibitor of pp2a to induce growth inhibition and apoptosis in breast cancer cells
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948957/
https://www.ncbi.nlm.nih.gov/pubmed/27574003
http://dx.doi.org/10.3892/ijo.2016.3588
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