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 (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.

High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer

“…Cancer cells demonstrate high proliferating capabilities and require constant biosynthesis of macromolecules as building blocks for the generation of new cells, thereby resulting in a high-energy demand for cancer cells (14). ERRα demonstrates key regulatory roles in a variety of malignant processes, including proliferation, invasion, metastasis and chemotherapy resistance (15)(16)(17). Since ERRα serves a crucial role in cancer initiation, development and progression, it may be speculated that ERRα holds significant clinical significance for patients with cancer.…”

Estrogen-related receptor α participates transforming growth factor-β (TGF-β) induced epithelial-mesenchymal transition of osteosarcoma cells

“…4 Our results confirmed the study that the expression of ERRa is correlated with osteosarcoma progression. 6 Considering that ERRa can activate Snail via both transcriptional and posttranscriptional mechanisms, 16 whether ERRa can regulate the stability of Snail protein also needs further studies in osteosarcoma cells.…”

“…4 Further, it can confer methotrexate resistance via attenuation of reactive oxygen species (ROS) production in OS cells. 6 However, the roles of ERRa in OS progression and whether it is related to EMT process are still not studied.…”

Suppression of microRNA-18a expression inhibits invasion and promotes apoptosis of human trophoblast cells by targeting the estrogen receptor α gene

“…The expression of miR-18a was negatively correlated with ESRα expression in pre-eclampsia, which suggests that miR-18a is involved in the pathogenesis of pre-eclampsia, via negative regulation of ESRα expression (8)(9)(10)(11)(12)(13). Recent studies have shown that ESRα expression is involved in cell apoptosis (23), and that a change in cell apoptosis is associated with the pathogenesis of pre-eclampsia (24). Therefore, the low expression of miR-18a may affect trophoblast cell apoptosis by regulating ESRα expression, which may contribute to pre-eclampsia.…”