Estrogen-Related Receptor Alpha Confers Methotrexate Resistance via Attenuation of Reactive Oxygen Species Production and P53 Mediated Apoptosis in Osteosarcoma Cells
Estrogen-Related Receptor Alpha Confers Methotrexate Resistance via Attenuation of Reactive Oxygen Species Production and P53 Mediated Apoptosis in Osteosarcoma Cells
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雌激素相关受体 Alpha 通过减弱骨肉瘤细胞中活性氧的产生和 P53 介导的细胞凋亡来赋予甲氨蝶呤耐药性
DOI：
10.1155/2014/616025
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发表时间：
2014-01-01
影响因子：
--
通讯作者：
Wang, Junjian
中科院分区：
文献类型：
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作者：
Chen, Peng;Wang, Haibin;Wang, Junjian
骨肉瘤（osteosarcoma，OS）是一种好发于儿童和青少年的恶性肿瘤。甲氨蝶呤（MTX）是一种广泛用于治疗骨肉瘤的化疗药物，但由于获得性耐药而导致治疗失败的情况很常见，其分子机制尚不清楚。在这项研究中，我们报告说，雌激素相关受体α（ERR α），孤儿核受体的过度表达，促进细胞存活，并阻止MTX诱导的细胞死亡U2OS细胞。我们发现MTX诱导MTX敏感的U2OS细胞产生ROS，而ERR α有效地阻断ROS产生和ROS相关的细胞凋亡。我们的进一步研究表明ERR α抑制了ROS对肿瘤抑制因子P53及其靶基因NOXA和XAF 1的诱导，而NOXA和XAF 1是P53依赖性凋亡的介导因子。总之，本研究表明ERR α通过阻断MTX诱导的ROS产生和减弱p53介导的凋亡信号通路的激活在MTX耐药的发展中起重要作用，并指出ERR α作为改善骨肉瘤治疗的新靶点。
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 alpha), 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 alpha effectively blocked the ROS production and ROS associated cell apoptosis. Our further studies demonstrated that ERR alpha 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 alpha 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 alpha as a novel target for improving osteosarcoma therapy.