Okoh V O, Garba N A, Penney R B, Das J, Deoraj A, Singh K P, Sarkar S, Felty Q, Yoo C, Jackson R M, Roy D
Department of Environmental and Occupational Health, Florida International University, 11200 SW 8th Street, Miami, FL 33199-0001, USA.
Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72204, USA.
Br J Cancer. 2015 May 12;112(10):1687-702. doi: 10.1038/bjc.2014.586.
17β-Oestradiol (E2)-induced reactive oxygen species (ROS) have been implicated in regulating the growth of breast cancer cells. However, the underlying mechanism of this is not clear. Here we show how ROS through a novel redox signalling pathway involving nuclear respiratory factor-1 (NRF-1) and p27 contribute to E2-induced growth of MCF-7 breast cancer cells.
Chromatin immunoprecipitation, qPCR, mass spectrometry, redox western blot, colony formation, cell proliferation, ROS assay, and immunofluorescence microscopy were used to study the role of NRF-1.
The major novel finding of this study is the demonstration of oxidative modification of phosphatases PTEN and CDC25A by E2-generated ROS along with the subsequent activation of AKT and ERK pathways that culminated in the activation of NRF-1 leading to the upregulation of cell cycle genes. 17β-Oestradiol-induced ROS by influencing nuclear proteins p27 and Jab1 also contributed to the growth of MCF-7 cells.
Taken together, our results present evidence in the support of E2-induced ROS-mediated AKT signalling leading to the activation of NRF-1-regulated cell cycle genes as well as the impairment of p27 activity, which is presumably necessary for the growth of MCF-7 cells. These observations are important because they provide a new paradigm by which oestrogen may contribute to the growth of breast cancer.
17β-雌二醇（E2）诱导产生的活性氧（ROS）被认为参与调节乳腺癌细胞的生长。然而，其潜在机制尚不清楚。在此，我们展示了ROS如何通过一条涉及核呼吸因子-1（NRF-1）和p27的新型氧化还原信号通路促进E2诱导的MCF-7乳腺癌细胞生长。
采用染色质免疫沉淀、qPCR、质谱分析、氧化还原蛋白质印迹、集落形成、细胞增殖、ROS检测及免疫荧光显微镜技术研究NRF-1的作用。
本研究的主要新发现是，E2产生的ROS对磷酸酶PTEN和CDC25A进行氧化修饰，随后激活AKT和ERK通路，最终激活NRF-1，导致细胞周期基因上调。17β-雌二醇通过影响核蛋白p27和Jab1诱导产生的ROS也促进了MCF-7细胞的生长。
综上所述，我们的结果表明，E2诱导的ROS介导的AKT信号传导导致NRF-1调控的细胞周期基因激活以及p27活性受损，这可能是MCF-7细胞生长所必需的。这些观察结果很重要，因为它们提供了一种雌激素可能促进乳腺癌生长的新范例。
