Dexamethasone Downregulates SLC7A5 Expression and Promotes Cell Cycle Arrest, Autophagy and Apoptosis in BeWo Cells
Dexamethasone Downregulates SLC7A5 Expression and Promotes Cell Cycle Arrest, Autophagy and Apoptosis in BeWo Cells
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DOI：
10.1002/jcp.25076
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发表时间：
2016-01-01
影响因子：
5.6
通讯作者：
Zhao, Ruqian
中科院分区：
文献类型：
--
作者：
He, Bin;Zhang, Nana;Zhao, Ruqian
合成糖皮质激素（GCs）如地塞米松（Dex）被广泛给予孕妇，以诱导成熟和提高早产儿的生存能力。尽管对胎盘有益，但合成GCs对胎盘生长和营养转运系统有不利影响。然而，涉及这些事件的分子机制仍然未知。本研究以人胎盘绒毛膜癌细胞系（BeWo）为模型，探讨在Dex胁迫下氨基酸转运与细胞活力之间的联系途径。Dex （100nM）作用24h后，BeWo细胞出现G1/S细胞周期阻滞，细胞自噬和凋亡增强。同时，氨基酸载体SLC7A5下调与细胞氨基酸摄取受损和哺乳动物雷帕霉素靶（mTOR）信号传导抑制有关。BCH（一种经典的System L抑制剂，能使SLC7A5失活）处理的BeWo细胞也出现了类似的细胞反应。糖皮质激素受体（GR）拮抗剂RU486能够减少dex诱导的GR向细胞核的易位，并消除这些影响。此外，Dex处理显著促进GR与SLC7A5基因近端启动子序列的结合。综上所述，我们的研究结果表明，Dex通过gr介导的转抑制下调SLC7A5的表达。氨基酸摄取受损导致mTOR信号传导抑制，从而导致BeWo细胞增殖抑制，自噬和凋亡增强。这些发现表明SLC7A5介导了Dex对细胞活力的影响，为预防和治疗Dex诱导的胎盘细胞周期阻滞和凋亡提供了新的分子靶点。j .细胞。中国生物医学工程学报，2016,31(2):557 - 557。(c) 2015 Wiley期刊公司
Synthetic glucocorticoids (GCs) such as dexamethasone (Dex) are widely given to pregnant women to induce maturation and improve viability of preterm infants. Despite the beneficial effects, synthetic GCs have adverse effects on placental growth and nutrient transport system. However, the molecular mechanisms involved in these events remain unknown. Here we use a human placental choriocarcinoma cell line (BeWo) as model to explore the pathway linking amino acids transport with cell viability under Dex challenge. BeWo cells treated with Dex (100nM) for 24h demonstrated G1/S cell cycle arrest together with enhanced autophagy and apoptosis. Concurrently, the amino acid carrier SLC7A5 was down-regulated in association with impaired cellular amino acids uptake and inhibition of mammalian target of rapamycin (mTOR) signaling. Similar cellular responses were observed in BeWo cells treated with BCH, a classical System L inhibitor which inactivates SLC7A5. The glucocorticoid receptor (GR) antagonist RU486 was able to diminish Dex-induced translocation of GR into nucleus and to abolish these effects. Furthermore, Dex treatment significantly promoted the binding of GR to the proximal promoter sequence of SLC7A5 gene. Taken together, our results show that Dex downregulates SLC7A5 expression via GR-mediated transrepression. The impaired amino acids uptake leads to inhibition of mTOR signaling which in turn causes inhibited proliferation and enhanced autophagy and apoptosis in BeWo cells. These findings indicate that SLC7A5 mediates the effect of Dex on cell viability, thus providing a novel molecular target for the prevention and treatment of Dex-induced cell cycle arrest and apoptosis in placental cells. J. Cell. Physiol. 230: 233-242, 2016. (c) 2015 Wiley Periodicals, Inc.