Abstract
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.