Glutamine depletion and glucose depletion trigger growth inhibition via distinctive gene expression reprogramming
Glutamine depletion and glucose depletion trigger growth inhibition via distinctive gene expression reprogramming
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DOI：
10.4161/cc.21944
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发表时间：
2012-10-01
期刊：
影响因子：
4.3
通讯作者：
Sang, Nianli
中科院分区：
文献类型：
--
作者：
Qie, Shuo;Liang, Dongming;Sang, Nianli
谷氨酰胺（Gln）和葡萄糖（Glc）代表增殖细胞的两种重要营养素，这与致癌过程与增强的糖酵解和精氨酸分解相关的观察结果一致。已显示Gln消耗和Glc消耗触发生长停滞并最终导致细胞死亡。实体瘤通常生长超过血液供应，导致缺血，这与缺氧和营养不足有关。虽然氧传感和缺氧的适应机制已经得到了很好的研究，但细胞如何直接感知和响应Gln和Glc不足仍不清楚。利用mRNA表达谱分析技术，我们比较了急性Gln耗尽细胞、Glc耗尽细胞和适应Gln耗尽的细胞的基因表达谱。在这里，我们报告了在规定的营养条件下培养的细胞中基因表达的总体变化。mRNA分析数据显示，Gln和Glc耗尽引发了显着的基因表达重编程。Gln或Glc缺失都会导致细胞周期基因表达的变化，但这些条件对转录调节因子和基因表达谱有独特的影响。此外，Gln和Glc耗竭引发可区分的ER应激反应。基因表达模式支持Gln和Glc在支持细胞存活和增殖中具有独特的代谢作用，并且细胞使用不同的机制来感知和响应Gln和Glc不足。我们的mRNA分析数据库提供了一个资源，进一步研究营养感应机制和潜在的影响，葡萄糖和谷氨酰胺丰度对细胞的生物学行为。
Glutamine (Gln) and glucose (Glc) represent two important nutrients for proliferating cells, consistent with the observations that oncogenic processes are associated with enhanced glycolysis and glutaminolysis. Gln depletion and Glc depletion have been shown to trigger growth arrest and eventually cell death. Solid tumors often outgrow the blood supply, resulting in ischemia, which is associated with hypoxia and nutrient insufficiency. Whereas oxygen-sensing and adaptive mechanisms to hypoxia have been well-studied, how cells directly sense and respond to Gln and Glc insufficiency remains unclear. Using mRNA profiling techniques, we compared the gene expression profiles of acute Gln-depleted cells, Glc-depleted cells and cells adapted to Gln depletion. Here we report the global changes of the gene expression in those cells cultured under the defined nutrient conditions. Analysis of mRNA profiling data revealed that Gln and Glc depletion triggered dramatic gene expression reprogramming. Either Gln or Glc deletion leads to changes of the expression of cell cycle genes, but these conditions have distinctive effects on transcription regulators and gene expression profiles. Moreover, Gln and Glc depletion triggered distinguishable ER-stress responses. The gene expression patterns support that Gln and Glc have distinctive metabolic roles in supporting cell survival and proliferation, and cells use different mechanisms to sense and respond to Gln and Glc insufficiency. Our mRNA profiling database provides a resource for further investigating the nutrient-sensing mechanisms and potential effects of Glc and Gln abundance on the biological behaviors of cells.