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首页> 外文期刊>Biology Open >Blockage of glutamine-dependent anaplerosis affects mTORC1/2 activity and ultimately leads to cellular senescence-like response
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Blockage of glutamine-dependent anaplerosis affects mTORC1/2 activity and ultimately leads to cellular senescence-like response

机译：谷氨酰胺依赖性动脉粥样硬化的阻滞影响mTORC1 / 2活性并最终导致细胞衰老样反应

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The purpose of study was to explore the role of glutamine-dependent anaplerosis in cell fate determination (proliferation and senescence) and the potential associated mechanism by employing a pharmacological inhibitor of glutamine-dependent anaplerosis, amino-oxyacetate (AOA). Using the WI38 normal human embryonic fibroblast cell line, we found that exposure to AOA induced mTORC1 inactivation?mTORC2 activation (within day 1), cell cycle arrest (day 2–6) and cellular senescence (day 4–6). These AOA effects were blocked by concomitantly providing anaplerotic factors [α-ketoglutarate (αKG), pyruvate or oxaloacetate], and not affected by ROS scavenger N-acetyl-cysteine (NAC). Moreover, AOA-induced cellular senescence in WI38 cells is associated with elevated protein levels of p53, p21CIP1and p16INK4Aand decreased Rb protein level, which was blocked by αKG supplementation. In p16INK4A-deficient U2OS human osteosarcoma cells and p16INK4A-knockdown WI38 cells, AOA exposure also induced similar effects on cell proliferation, and protein level of P-Rb-S807/811 and Rb. Interestingly, no AOA induction of cellular senescence was observed in U2OS cells, yet was still seen in p16INK4A-knockdown WI38 cells accompanied by the presence of p16 antibody-reactive p12. In summary, we disclose that glutamine-dependent anaplerosis is essential to cell growth and closely associated with mTORC1 activation and mTORC2 inactivation, and impedes cellular senescence particularly associated with p16INK4A.
机译：该研究的目的是通过使用谷氨酰胺依赖性血管紧张素的药理抑制剂氨基-氧乙酸盐（AOA）来探索谷氨酰胺依赖性血管紧张素在细胞命运测定（增殖和衰老）中的作用以及潜在的相关机制。使用WI38正常人胚胎成纤维细胞系，我们发现暴露于AOA会诱导mTORC1失活→mTORC2活化（在第1天之内），细胞周期停滞（第2-6天）和细胞衰老（第4-6天）。这些AOA的作用可通过同时提供动脉粥样硬化因子[α-酮戊二酸（αKG），丙酮酸或草酰乙酸]来阻止，并且不受ROS清除剂N-乙酰半胱氨酸（NAC）的影响。此外，AOA诱导的WI38细胞衰老与p53，p21CIP1和p16INK4A的蛋白质水平升高和Rb蛋白质水平降低有关，这被αKG补充所阻止。在缺乏p16INK4A的U2OS人骨肉瘤细胞和p16INK4A抑制型WI38细胞中，暴露于AOA也会对细胞增殖以及P-Rb-S807 / 811和Rb的蛋白质水平产生相似的影响。有趣的是，在U2OS细胞中未观察到AOA诱导的细胞衰老，但在伴随p16抗体反应性p12的存在的p16INK4A敲低WI38细胞中仍未见到。总而言之，我们公开了谷氨酰胺依赖性动脉粥样硬化对于细胞生长是必不可少的，并且与mTORC1激活和mTORC2失活密切相关，并阻止细胞衰老，特别是与p16INK4A相关的细胞衰老。

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