Estrogen-related receptor α (ERRα) inverse agonist XCT-790 induces cell death in chemotherapeutic resistant cancer cells

Estrogen-related receptor alpha (ERRα) is primarily thought to regulate energy homeostasis through interacting with peroxisome proliferator-activated receptor γ coactivator-1α and -1β (PGC-1α and -1β). They coordinately control the transcription of genes in the oxidative phosphorylation pathway. In addition to its role in energy metabolism, ERRα has also been implicated as a prognostic marker for breast, ovarian, colon and prostate cancers. In this study, we found that an ERRα inverse agonist XCT-790 induced cell death in HepG2 hepatocarcinoma and its multi-drug resistance (MDR) sub-line R-HepG2. Using a dye Mitotracker Green which stains mitochondrion independent of mitochondrial membrane potential (ΔΨ m), we found that XCT-790 dose-dependently decreased mitochondrial mass. Intriguingly, XCT-790 increased ΔΨ m upon short term treatment but decreased ΔΨ m upon longer term treatment. The changes of ΔΨ m in turn promoted the production of reactive oxygen species (ROS) and led to ROS-mediated caspases 3/7, 8, 9 activation and cell death. Importantly, we established that an anti-oxidative compound Mn(III) Tetra(4-benzoic acid) porphyrin chloride (MnTBAP) blocked the caspases activities and cell death increased by XCT-790 treatment. Finally, we found that XCT-790 synergized with paclitaxel to induce cell death in multi-drug resistance sub-line R-HepG2. Our results provide a conceptual framework for further developing chemotherapeutics based on suppressing ERRα activity.