Dexamethasone may inhibit placental growth by blocking glucocorticoid receptors via phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin and reactive oxygen species/AMP-activated protein kinase signalling pathways in human placental JEG-3 cells
2021
Zhan, Xin | Xie, Yiran | Sun, Liping | Si, Qi | Shang, Hongkai
This study explored the molecular mechanism underlying the effects of dexamethasone (DEX, 1 µM) on glucose transporters (GLUT) in JEG-3 human placental choriocarcinoma cells. JEG-3 cells were treated with DEX, an expression plasmid encoding human glucocorticoid receptor α (GRα), pcDNA3.1-GRα, GRα short interference (si) RNA, LY294002, xanthine oxidase (XO)/hypoxanthine (HX), rapamycin, insulin-like growth factor (IGF) 1, N-acetylcysteine (NAC) or phosphatidic acid (PA), and cell proliferation, apoptosis, mitochondrial membrane potential (MMP), human chorionic gonadotrophin (hCG) content, human placental lactogen (hPL) content, glucose uptake, reactive oxygen species levels and signalling pathway modulation were evaluated. Treatment of JEG-3 cells with DEX (1 µM), GRα siRNA, LY294002 (50 µM), XO/HX (7.2 µM/36 nM) or rapamycin (80 nM) inhibited cell proliferation, induced apoptosis, significantly decreased MMP and hCG and hPL content and increased ROS levels. In addition, glucose uptake was decreased through downregulation of the mRNA and protein expression of GRα, GLUT1 and GLUT3. Treatment of JEG-3 cells with GRα siRNA, LY294002, XO/HX or rapamycin inhibited phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt, glycogen synthase kinase 3 and mammalian target of rapamycin (mTOR) and induced the phosphorylation of AMP-activated protein kinase (AMPK) and tuberous sclerosis complex 2. The effects of GRα overexpression and IGF1 (100 nM), NAC (5 nM) or PA (100 µM) treatment on JEG-3 cells contrasted with those of DEX treatment. DEX blocked glucose uptake by downregulating GRα expression, which reduced GLUT1 and GLUT3 mRNA and protein expression, which, in turn, may have inhibited the PI3K/AKT/mTOR pathway and activated the ROS/AMPK pathway.
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