International Journal of Oncology, 2016, 49(3):1203-1210.

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

Qingxia Zhao, Ming Zhao, Amanda B. Parris, et al

Basic Medical College of Zhengzhou University, Zhengzhou, Henan 450001, P.R. China; Julius L. Chambers Biomedical/Biotechnology Research Institute and Department of Biology, North Carolina Central University, Kannapolis, NC 28081, USA

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.

希腊《国际肿瘤杂志》2016, 49(3):1203-1210.

染料木黄酮靶向抑制乳腺癌细胞PP2A的生长抑制和诱导细胞凋亡

赵青霞，赵明等

郑州大学基础医学院，河南郑州450001; Julius L. Chambers生物医学/生物技术研究所和北卡罗来纳中央大学生物系，Kannapolis，NC 28081，美国

染料木黄酮是具有植物雌激素和酪氨酸激酶抑制性质的大豆异黄酮。高摄入量的大豆/染料木素与降低乳腺癌风险有关。尽管染料木素介导的抗肿瘤研究的进展，潜在的机制仍不清楚。在本研究中，我们调查染料木素诱导调节蛋白磷酸酶2A（CIP2A），是癌性抑制药物，蛋白磷酸酶2A（CIP2A）是一种新型致癌基因在乳腺癌中频繁过表达，染料木素对其诱导的生长抑制和细胞凋亡的功能影响。我们证明染料木黄酮诱导下调的CIP2A在MCF-7-C3和T47D乳腺癌细胞，这与其生长抑制和凋亡活动相关。染料木素能够降低CIP2A的过表达和敏化，诱导生长抑制和凋亡。我们进一步表明染料木素诱导下调的CIP2A涉及转录抑制和蛋白酶体降解。特别地，在较高浓度的染料木黄酮诱导E2F1和CIP2A的同时下调。E2F1的过表达减毒染料木素诱导CIP2A mRNA的下调，表明E2F1在染料木黄酮诱导的CIP2A的转录抑制中的作用。总之，我们的研究结果确定CIP2A作为染料木素的功能目标，并表明调节E2F1介导的CIP2A转录调控有助于其下调。这些数据推进我们对染料木素诱导的生长抑制和凋亡的理解，并支持对CIP2A作为相关抗癌剂的治疗靶点的进一步研究。