title: Estrogen-related receptor alpha confers methotrexate resistance via attenuation of reactive oxygen species production and P53 mediated apoptosis in osteosarcoma cells.
abstract: 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 (ERR α ), 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 ERR α effectively blocked the ROS production and ROS associated cell apoptosis. Our further studies demonstrated that ERR α 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 ERR α 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 ERR α as a novel target for improving osteosarcoma therapy.
authors: First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China ; Cancer Center, University of California, Davis, Sacramento, CA 95817, USA.
authors: Peng
authors: P
authors: Chen
authors: State Key Hip Joints Center, First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 12 Jichang Road, Guangzhou, Guangdong 510405, China.
authors: Haibin
authors: H
authors: Wang
authors: Cancer Center, University of California, Davis, Sacramento, CA 95817, USA.
authors: Zhijian
authors: Z
authors: Duan
authors: Cancer Center, University of California, Davis, Sacramento, CA 95817, USA.
authors: June X
authors: JX
authors: Zou
authors: Cancer Center, University of California, Davis, Sacramento, CA 95817, USA.
authors: Hongwu
authors: H
authors: Chen
authors: State Key Hip Joints Center, First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 12 Jichang Road, Guangzhou, Guangdong 510405, China.
authors: Wei
authors: W
authors: He
authors: Cancer Center, University of California, Davis, Sacramento, CA 95817, USA.
authors: Junjian
authors: 0000-0001-8376-5233
authors: J
authors: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008727:Methotrexate / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008727:Methotrexate; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D000097983:ERRalpha Estrogen-Related Receptor; C498702:PMAIP1 protein, human; C495901:TP53 protein, human; C417551:XAF1 protein, human