PI3K/AKT phosphorylation activates ERRα by upregulating PGC‑1α and PGC‑1β in gallbladder cancer
- Lei Wang
- Mengmeng Yang
- Huihan Jin
Affiliations: Department of Hepatobiliary Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, Jiangsu 214002, P.R. China, Department of Malaria Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology (Jiangsu Institute of Parasitic Diseases), Wuxi, Jiangsu 214002, P.R. China
- Published online on: June 28, 2021 https://doi.org/10.3892/mmr.2021.12252
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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.