title: Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells.
abstract: 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.
authors: Basic Medical College of Zhengzhou University, Zhengzhou, Henan 450001, P.R. China.
authors: Qingxia
authors: Q
authors: Zhao
authors: Julius L. Chambers Biomedical/Biotechnology Research Institute and Department of Biology, North Carolina Central University, Kannapolis, NC 28081, USA.
authors: Ming
authors: M
authors: Zhao
authors: Julius L. Chambers Biomedical/Biotechnology Research Institute and Department of Biology, North Carolina Central University, Kannapolis, NC 28081, USA.
authors: Amanda B
authors: AB
authors: Parris
authors: Basic Medical College of Zhengzhou University, Zhengzhou, Henan 450001, P.R. China.
authors: Ying
authors: Y
authors: Xing
authors: Julius L. Chambers Biomedical/Biotechnology Research Institute and Department of Biology, North Carolina Central University, Kannapolis, NC 28081, USA.
authors: Xiaohe
authors: X
authors: Yang
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D001324:Autoantigens; C500266:CIP2A protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019833:Genistein