JCI：鉴别出治疗肺癌的潜在靶点

  发表在国际杂志the Journal of Clinical Investigation上的一篇研究论文中，来自肯塔基大学Markey癌症中心的研究人员通过研究发现，靶向作用一种关键酶类及其相关的代谢程序或许会帮助开发治疗肺癌的新型药物。癌细胞往往都会通过改变代谢来满足自身对能量的需求从而持续生长，细胞中线粒体的三羧酸循环被用于供给能量及细胞生长所需要的原料，而线粒体中的两种酶类：丙酮酸羧化酶（PC）和谷氨酰胺酶可以补充三羧酸循环中的碳。

  文章中，研究人员收集了超过120名肺癌患者的机体代谢数据，同时研究人员也测定了早期肺癌患者机体中丙酮酸羧化酶（PC）和谷氨酰胺酶的活性水平；当在对患者进行手术移除肿瘤组织前，研究人员给患者输入一种用稳定重原子标记的葡萄糖，结果发现丙酮酸羧化酶可以被选择性激活，换句话说，丙酮酸羧化酶的表达在肺癌发生中扮演着重要角色。

  利用分子遗传工具来减少肺癌患者细胞中的丙酮酸羧化酶水平，研究者发现细胞生长降低了，而因癌细胞中央代谢的改变引发的丙酮酸羧化酶水平的缺失也正揭示了丙酮酸羧化酶在癌细胞早期代谢重编程阶段的重要作用。

  最后研究者Fan说道，我们都知道在患者机体中癌症组织会发生代谢重编程，尤其是丙酮酸羧化酶的激活对于肺癌细胞生长和生存至关重要，因此，揭示如何通过靶向作用丙酮酸羧化酶来帮助开发新型有效的改善肺癌的疗法或许可以有效治疗患者。（转化医学网360zhyx.com）

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转化医学网推荐的原文摘要：

Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation
JCI doi:10.1172/JCI72873
Katherine Sellers1,6, Matthew P. Fox2, Michael Bousamra, II2,5, Stephen P. Slone3, Richard M. Higashi1,4,7, Donald M. Miller5, Yali Wang5, Jun Yan5, Mariia O. Yuneva6, Rahul Deshpande7, Andrew N. Lane4,5,7 and Teresa W.-M. Fan1,4,5,7
Anabolic biosynthesis requires precursors supplied by the Krebs cycle, which in turn requires anaplerosis to replenish precursor intermediates. The major anaplerotic sources are pyruvate and glutamine, which require the activity of pyruvate carboxylase (PC) and glutaminase 1 (GLS1), respectively. Due to their rapid proliferation, cancer cells have increased anabolic and energy demands; however, different cancer cell types exhibit differential requirements for PC- and GLS-mediated pathways for anaplerosis and cell proliferation. Here, we infused patients with early-stage non–small-cell lung cancer (NSCLC) with uniformly 13C-labeled glucose before tissue resection and determined that the cancerous tissues in these patients had enhanced PC activity. Freshly resected paired lung tissue slices cultured in 13C6-glucose or 13C5,15N2-glutamine tracers confirmed selective activation of PC over GLS in NSCLC. Compared with noncancerous tissues, PC expression was greatly enhanced in cancerous tissues, whereas GLS1 expression showed no trend. Moreover, immunohistochemical analysis of paired lung tissues showed PC overexpression in cancer cells rather than in stromal cells of tumor tissues. PC knockdown induced multinucleation, decreased cell proliferation and colony formation in human NSCLC cells, and reduced tumor growth in a mouse xenograft model. Growth inhibition was accompanied by perturbed Krebs cycle activity, inhibition of lipid and nucleotide biosynthesis, and altered glutathione homeostasis. These findings indicate that PC-mediated anaplerosis in early-stage NSCLC is required for tumor survival and proliferation.