Altered regulation of metabolic pathways in human lung cancer discerned by (13)C stable isotope-resolved metabolomics (SIRM).
Altered regulation of metabolic pathways in human lung cancer discerned by (13)C stable isotope-resolved metabolomics (SIRM).
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DOI：
10.1186/1476-4598-8-41
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发表时间：
2009-06-26
期刊：
影响因子：
37.3
通讯作者：
Miller DM
中科院分区：
文献类型：
--
作者：
Fan TW;Lane AN;Higashi RM;Farag MA;Gao H;Bousamra M;Miller DM
由恶性转化引起的代谢紊乱尚未在人肺癌原位中系统地表征。稳定同位素分解代谢组学分析（SIRM）能够分析肺癌基因失调的功能。为此，我们通过将均匀标记的13c -葡萄糖注入人肺癌患者体内，然后切除和处理配对的非癌性肺组织和非小细胞癌组织，来研究代谢变化。采用核磁共振（NMR）和气相色谱-质谱（GC-MS）对组织和血浆提取物进行13c -同位素代谢组学分析。许多初级代谢物在肺癌组织中的含量始终高于其周围的非癌组织。在肿瘤中，乳酸、Ala、琥珀酸、谷氨酸、Asp和柠檬酸中13c的富集也较高，表明肿瘤组织中糖酵解和克雷布斯循环更为活跃。特别值得注意的是，在肺肿瘤组织中，含有三个13c标记碳的Asp同位素体的产生增强，13c -2,3- glu同位素体的形成。这与葡萄糖通过糖酵解、丙酮酸羧基化（PC）和克雷布斯循环转化为Asp或Glu是一致的。肿瘤组织中丙酮酸羧化酶mRNA和蛋白水平的升高也表明PC活化。PC激活-首次在人类受试者中发现-可能对补充克雷布斯循环中间体很重要，克雷布斯循环中间体可以转移到脂质，蛋白质和核酸的生物合成中，以满足肺肿瘤组织生长的高合成代谢需求。我们假设这在非小细胞肺癌和其他肿瘤的发展中是一个重要的事件。
Metabolic perturbations arising from malignant transformation have not been systematically characterized in human lung cancers in situ. Stable isotope resolved metabolomic analysis (SIRM) enables functional analysis of gene dysregulations in lung cancer. To this purpose, metabolic changes were investigated by infusing uniformly labeled 13C-glucose into human lung cancer patients, followed by resection and processing of paired non-cancerous lung and non small cell carcinoma tissues. NMR and GC-MS were used for 13C-isotopomer-based metabolomic analysis of the extracts of tissues and blood plasma. Many primary metabolites were consistently found at higher levels in lung cancer tissues than their surrounding non-cancerous tissues. 13C-enrichment in lactate, Ala, succinate, Glu, Asp, and citrate was also higher in the tumors, suggesting more active glycolysis and Krebs cycle in the tumor tissues. Particularly notable were the enhanced production of the Asp isotopomer with three 13C-labeled carbons and the buildup of 13C-2,3-Glu isotopomer in lung tumor tissues. This is consistent with the transformations of glucose into Asp or Glu via glycolysis, anaplerotic pyruvate carboxylation (PC), and the Krebs cycle. PC activation in tumor tissues was also shown by an increased level of pyruvate carboxylase mRNA and protein. PC activation – revealed here for the first time in human subjects – may be important for replenishing the Krebs cycle intermediates which can be diverted to lipid, protein, and nucleic acid biosynthesis to fulfill the high anabolic demands for growth in lung tumor tissues. We hypothesize that this is an important event in non-small cell lung cancer and possibly in other tumor development.
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影响因子：
7.4
作者：
Broeckling, Corey D.;Reddy, Indira R.;Sumner, Lloyd W.
通讯作者：
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作者：
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