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 (ΔΨm), we found that XCT-790 dose-dependently decreased mitochondrial mass. Intriguingly, XCT-790 increased ΔΨm upon short term treatment but decreased ΔΨm upon longer term treatment. The changes of ΔΨm 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.