Huang Li, Zhang Cheng, Su Li, Song Zhengyu
Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
Biochem Biophys Res Commun. 2017 May 6;486(3):744-751. doi: 10.1016/j.bbrc.2017.03.113. Epub 2017 Mar 22.
While TGF-β1 is known to induce epithelial-mesenchymal transition (EMT), a major factor in the pathogenesis of proliferative vitreoretinopathy (PVR), in ARPE-19 cells. The molecular pathways involved in EMT formation have not yet to be fully characterized. In this study, we have found that TGF-β1-mediated induction of EMT in ARPE-19 cells varied in a dose- and time-dependent manner. Specifically, TGF-β1 inhibited GSK-3β by accelerating phosphorylation at ser9. GSK-3β inhibitor or knockdown of GSK-3β resulted in enhanced TGF-β1-mediated EMT, migration and collagen contraction in ARPE-19 cells, which were then abrogated by GSK-3β overexpression and PI3K/AKT inhibitor. Importantly, GSK-3β also mediated metabolic reprogramming in TGF-β1-treated cells. Our results indicate that GSK-3β plays a pivotal role in TGF-β1-mediated EMT in ARPE-19 cells.
虽然已知转化生长因子-β1（TGF-β1）可在ARPE - 19细胞中诱导上皮-间质转化（EMT），这是增殖性玻璃体视网膜病变（PVR）发病机制中的一个主要因素。但参与EMT形成的分子途径尚未完全明确。在本研究中，我们发现TGF-β1介导的ARPE - 19细胞中EMT的诱导呈剂量和时间依赖性变化。具体而言，TGF-β1通过加速丝氨酸9位点的磷酸化来抑制糖原合成酶激酶-3β（GSK-3β）。GSK-3β抑制剂或GSK-3β基因敲低导致ARPE - 19细胞中TGF-β1介导的EMT、迁移和胶原收缩增强，而GSK-3β过表达和磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/AKT）抑制剂可消除这些作用。重要的是，GSK-3β还介导了TGF-β1处理细胞中的代谢重编程。我们的结果表明，GSK-3β在TGF-β1介导的ARPE - 19细胞EMT中起关键作用。
