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BioMed Research International
Volume 2014 (2014), Article ID 616025, 9 pages
Research Article

Estrogen-Related Receptor Alpha Confers Methotrexate Resistance via Attenuation of Reactive Oxygen Species Production and P53 Mediated Apoptosis in Osteosarcoma Cells

1First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
2Cancer Center, University of California, Davis, Sacramento, CA 95817, USA
3State Key Hip Joints Center, First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 12 Jichang Road, Guangzhou, Guangdong 510405, China

Received 26 March 2014; Accepted 25 April 2014; Published 19 May 2014

Academic Editor: Jianzhen Xu

Copyright © 2014 Peng Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Osteosarcoma (OS) is a malignant tumor mainly occurring in children and adolescents. Methotrexate (MTX), a chemotherapy agent, is widely used in treating OS. However, treatment failures are common due to acquired chemoresistance, for which the underlying molecular mechanisms are still unclear. In this study, we report that overexpression of estrogen-related receptor alpha (ERRα), an orphan nuclear receptor, promoted cell survival and blocked MTX-induced cell death in U2OS cells. We showed that MTX induced ROS production in MTX-sensitive U2OS cells while ERRα effectively blocked the ROS production and ROS associated cell apoptosis. Our further studies demonstrated that ERRα suppressed ROS induction of tumor suppressor P53 and its target genes NOXA and XAF1 which are mediators of P53-dependent apoptosis. In conclusion, this study demonstrated that ERRα plays an important role in the development of MTX resistance through blocking MTX-induced ROS production and attenuating the activation of p53 mediated apoptosis signaling pathway, and points to ERRα as a novel target for improving osteosarcoma therapy.