Estrogen-related receptor alpha confers methotrexate resistance via attenuation of reactive oxygen species production and P53 mediated apoptosis in osteosarcoma cells.

Peng Chen,Hongwu Chen,Junjian Wang,Haibin Wang,Wei He,June X Zou,Zhijian Duan

doi:10.1155/2014/616025

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 (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.

Highlights

Osteosarcoma (OS) is one of the most common forms of childhood and adolescent cancer, comprising approximately 20% of all primary bone cancers, which is the second leading cause of mortality in this age group [1, 2]
The use of neoadjuvant chemotherapy combined with surgical resection is the mainstay therapy in OS [3]
We demonstrated that elevated ERRα can result in the development of MTX resistance through blocking MTX-induced reactive oxygen species (ROS) production and attenuating p53-dependent apoptosis in osteosarcoma cells

Summary

Introduction

Osteosarcoma (OS) is one of the most common forms of childhood and adolescent cancer, comprising approximately 20% of all primary bone cancers, which is the second leading cause of mortality in this age group [1, 2]. In addition to its role in the control of energy metabolic processes, there is cumulative evidence showing potential functions of ERRα in cancer development and progress. Our previous reports have shown that ERRα suppression efficiently induced cancer cell death via induction of reactive oxygen species (ROS) production [11, 12]. ROS are chemically reactive molecules and have important roles in cell signaling and homeostasis [13]. Recent studies demonstrated that chemotherapeutic drugs including MTX can induce cell death by promoting ROS production [16, 17]. We demonstrated that elevated ERRα can result in the development of MTX resistance through blocking MTX-induced ROS production and attenuating p53-dependent apoptosis in osteosarcoma cells. Our study suggests ERRα is a novel target for improving osteosarcoma therapy

Materials and Methods

Results

Discussion