title: Estrogen-related receptor alpha (ERRalpha) inverse agonist XCT-790 induces cell death in chemotherapeutic resistant cancer cells.
abstract: 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.
authors.affiliation: Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Science City, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wu
authors.forename: Junjian
authors.initials: J
authors.lastname: Wang
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Wang
authors.forename: Tim-Tak
authors.initials: TT
authors.lastname: Kwok
authors.forename: Siu-Kai
authors.initials: SK
authors.lastname: Kong
authors.forename: Chiwai
authors.initials: C
authors.lastname: Wong
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000819:agonists*; D013844:Thiazoles / Q000494:pharmacology*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D020169:Caspases; D004272:DNA, Mitochondrial; D009570:Nitriles; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D013844:Thiazoles; D000097983:ERRalpha Estrogen-Related Receptor; C488234:XCT790