Estrogen-related receptor alpha (
ERRalpha) is primarily thought to regulate energy homeostasis through interacting with
peroxisome proliferator-activated receptor gamma coactivator-1alpha and -1beta (PGC-1alpha and -1beta). They coordinately control the transcription of genes in the oxidative phosphorylation pathway. In addition to its role in energy metabolism,
ERRalpha has also been implicated as a prognostic marker for breast, ovarian, colon and
prostate cancers. In this study, we found that an
ERRalpha 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 (DeltaPsi(m)), we found that
XCT-790 dose-dependently decreased mitochondrial mass. Intriguingly,
XCT-790 increased DeltaPsi(m) upon short term treatment but decreased DeltaPsi(m) upon longer term treatment. The changes of DeltaPsi(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
ERRalpha activity.