GlaxoSmithKline, Oncology Research, Cancer Metabolism, Collegeville, PA, USA.
Cancer Biol Ther. 2012 Oct;13(12):1185-94. doi: 10.4161/cbt.21348. Epub 2012 Aug 15.
One of the hallmarks of cancer is metabolic deregulation. Many tumors display increased glucose uptake and breakdown through the process of aerobic glycolysis, also known as the Warburg effect. Less studied in cancer development and progression is the importance of the glutamine (Gln) pathway, which provides cells with a variety of essential products to sustain cell proliferation, such as ATP and macromolecules for biosynthesis. To this end Gln dependency was assessed in a panel of non-small cell lung cancer lines (NSCLC). Gln was found to be essential for the growth of cells with high rates of glutaminolysis, and after exploring multiple genes in the Gln pathway, GLS1 was found to be the key enzyme associated with this dependence. This dependence was confirmed by observing the rescue of decreased growth by exogenous addition of downstream metabolites of glutaminolysis. Expression of the GLS1 splice variant KGA was found to be decreased in tumors compared with normal lung tissue. Transient knock down of GLS1 splice variants indicated that loss of GAC had the most detrimental effect on cancer cell growth. In conclusion, NSCLC cell lines depend on Gln for glutaminolysis to a varying degree, in which the GLS1 splice variant GAC plays an essential role and is a potential target for cancer metabolism-directed therapy.
癌症的一个标志是代谢失调。许多肿瘤通过有氧糖酵解（也称为Warburg 效应）过程显示出葡萄糖摄取和分解的增加。在癌症的发展和进展中，谷氨酰胺（Gln）途径的重要性研究较少，该途径为细胞提供了各种必需产物，以维持细胞增殖，如 ATP 和用于生物合成的大分子。为此，在一组非小细胞肺癌细胞系（NSCLC）中评估了 Gln 依赖性。发现 Gln 对于具有高谷氨酰胺分解率的细胞的生长是必需的，并且在探索 Gln 途径中的多个基因之后，发现 GLS1 是与这种依赖性相关的关键酶。通过观察外源性添加谷氨酰胺分解的下游代谢物对生长减少的挽救，证实了这种依赖性。与正常肺组织相比，在肿瘤中发现 GLS1 剪接变体 KGA 的表达降低。GLS1 剪接变体的瞬时敲低表明，GAC 的缺失对癌细胞生长的影响最大。总之，NSCLC 细胞系在不同程度上依赖 Gln 进行谷氨酰胺分解，其中 GLS1 剪接变体 GAC 起着至关重要的作用，是癌症代谢靶向治疗的潜在靶点。
