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.
Mol Med Rep. 2021 Aug;24(2). doi: 10.3892/mmr.2021.12252. Epub 2021 Jun 29.
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.
核雌激素相关受体-α（ERRα）是一种已被鉴定为转录因子的孤儿受体。过氧化物酶体增殖物激活受体-γ（PPARγ）共激活因子-1-α（PGC-1α）和 PPARγ 共激活因子-1-β（PGC-1β）作为 ERRα 的共激活因子。我们之前的研究报道，激活的 ERRα 通过促进 PI3K/AKT 磷酸化来促进胆囊癌细胞的侵袭和增殖。因此，本研究旨在探讨 PI3K/AKT 磷酸化是否可以在正反馈环中增强 ERRα 的活性。LY294002 和胰岛素样生长因子 I（IGF-I）分别用于抑制和促进 PI3K/AKT 磷酸化。使用 3X ERE-TATA 荧光素酶报告基因来测量 ERRα 活性。本研究发现，LY294002 抑制 PI3K/AKT 磷酸化，降低了 NOZ 细胞的增殖和侵袭，并抑制了 ERRα 的活性。相反，IGF-I 诱导 PI3K/AKT 磷酸化，促进了 NOZ 细胞的增殖和侵袭，并增强了 ERRα 的活性。IGF-I 和 LY294002 分别上调和下调了 PGC-1α 和 PGC-1β 的蛋白表达水平。此外，PGC-1α 和 PGC-1β 的敲低拮抗了由 PI3K/AKT 磷酸化增强的 ERRα 激活。综上所述，本研究表明，PI3K/AKT 磷酸化通过上调 NOZ 细胞中 PGC-1α 和 PGC-1β 的表达水平来触发 ERRα。
