Objective: Although oestrogen-related receptor a (ERRa) is primarily thought to regulate energy homeostasis, it also serves as a prognostic marker for cancer. The aim of this study was to investigate any connection between ERRa activity and cell popula-
tion growth. Materials and methods: ERRa activity was suppressed in human non-small cell lung cancer cells (NSCLC) A549 by a specific inverse agonist XCT-1 790. Gene expressions were detected using quantita-tive real-time PCR and Western blot analysis. Mitochondrial mass, membrane potential and reactive oxygen species (ROS) production were measured by staining with Mitotracker green, JC-1 and CM-H2DCFDA dyes respectively. Rate of progression through the tricarboxylic acid (TCA) cycle was analysed by measuring activities of citrate synthase and succinate dehydrogenase. Cell cycle analysis was performed by using flow cytometry.
Results: We found that XCT-790 treatment reduced mitochondrial mass but enhanced mitochondrial ROS production by increasing rate through the TCA cycle, elevating mitochondrial membrane potential (DWm) and down-regulating expression of superoxide dismutase. It was further demonstrated that XCT-790-induced ROS modulated p53 and Rb signalling pathways and suppressed cell replication.
Conclusions: ERRa affects cell cycle mechanisms through modulating mitochondrial mass and function. Dysregulation of this essential pathway leads to elevation in mitochondrial ROS production, which in turn modulates activities of tumour suppressors, resulting in cell cycle arrest.
