PI3K/AKT phosphorylation activates ERRα by upregulating PGC-1α and PGC-1β in gallbladder cancer

The nuclear estrogen-related receptor-α (ERRα) is an orphan receptor that has been identified as a transcriptional factor. Peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1-α (PGC-1α) and PPARγ coactivator-1-β (PGC-1β) act as the co-activators of ERRα. Our previous study reported that activated ERRα promoted the invasion and proliferation of gallbladder cancer cells by promoting PI3K/AKT phosphorylation. Therefore, the aim of the current study was to investigate whether PI3K/AKT phosphorylation could enhance ERRα activity in a positive feedback loop. LY294002 and insulin-like growth factor I (IGF-I) were used to inhibit and promote PI3K/AKT phosphorylation, respectively. A 3X ERE-TATA luciferase reporter was used to measure ERRα activity. The present study found that LY294002 inhibited PI3K/AKT phosphorylation, decreased the proliferation and invasion of NOZ cells and suppressed the activity of ERRα. Conversely, IGF-I induced PI3K/AKT phosphorylation, promoted the proliferation and invasion of NOZ cells and enhanced the activity of ERRα. The protein expression levels of PGC-1α and PGC-1β were elevated and reduced by IGF-I and LY294002, respectively. Moreover, knockdown of PGC-1α and PGC-1β antagonized ERRα activation, which was enhanced by PI3K/AKT phosphorylation. Taken together, the present study demonstrated that PI3K/AKT phosphorylation triggered ERRα by upregulating the expression levels of PGC-1α and PGC-1β in NOZ cells.