Metabolomic analysis of dynamic response and drug resistance of gastric cancer cells to 5-fluorouracil.
Metabolomic analysis of dynamic response and drug resistance of gastric cancer cells to 5-fluorouracil.
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DOI：
10.3892/or.2012.2182
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发表时间：
2013-03
期刊：
影响因子：
4.2
通讯作者：
Okada M
中科院分区：
文献类型：
--
作者：
Sasada S;Miyata Y;Tsutani Y;Tsuyama N;Masujima T;Hihara J;Okada M
代谢组学已发展成为癌症研究的重要新工具。它有望导致发现用于癌症诊断和治疗的生物标志物候选者。本研究旨在对人胃癌细胞对5-氟尿嘧啶（5-FU）的细胞内动态反应进行全面的代谢组学分析，并参考药物作用和耐药机制。采用液相色谱-质谱联用技术检测胃癌细胞和5-FU耐药细胞中的小分子代谢产物。根据5-FU治疗前后是否存在耐药选择候选药物靶点。此外，每个候选人的基因表达进行了评估，通过逆转录-聚合酶链反应。在5-FU短期治疗期间，癌细胞中代谢物的数量发生了显著变化。特别是，脯氨酸减少到原来水平的三分之一，谷氨酸增加了3个因素后，3小时的治疗。从脯氨酸代谢产生谷氨酸通过脯氨酸脱氢酶（PRODH）进行，产生超氧化物。5-FU治疗后，PRODH mRNA表达上调2倍，超氧化物的产生增加了3倍。在5-FU耐药细胞中，脯氨酸和谷氨酸水平的影响小于非耐药细胞，PRODH mRNA表达和超氧化物的产生没有增加治疗后。总之，作者使用代谢组学方法确定了药物作用的候选生物标志物PRODH，这一结果已通过常规方法得到证实。代谢组学将在未来的癌症研究领域发挥重要作用。
Metabolomics has developed as an important new tool in cancer research. It is expected to lead to the discovery of biomarker candidates for cancer diagnosis and treatment. The current study aimed to perform a comprehensive metabolomic analysis of the intracellular dynamic responses of human gastric cancer cells to 5-fluorouracil (5-FU), referencing the mechanisms of drug action and drug resistance. Small metabolites in gastric cancer cells and 5-FU-resistant cells were measured by liquid chromatography-mass spectrometry. Candidates for drug targets were selected according to the presence or absence of resistance, before and after 5-FU treatment. In addition, the gene expression of each candidate was assessed by reverse transcription-polymerase chain reaction. The number of metabolites in cancer cells dramatically changed during short-term treatment with 5-FU. Particularly, proline was reduced to one-third of its original level and glutamate was increased by a factor of 3 after 3 h of treatment. The metabolic production of glutamate from proline proceeds by proline dehydrogenase (PRODH), producing superoxide. After 5-FU treatment, PRODH mRNA expression was upregulated 2-fold and production of superoxide was increased by a factor of 3. In 5-FU-resistant cells, proline and glutamate levels were less affected than in non-resistant cells, and PRODH mRNA expression and superoxide generation were not increased following treatment. In conclusion, the authors identified a candidate biomarker, PRODH, for drug effects using a metabolomic approach, a result that was confirmed by conventional methods. In the future, metabolomics will play an important role in the field of cancer research.
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影响因子：
11.2
作者：
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