Metabolomic analysis of dynamic response and drug resistance of gastric cancer cells to 5-fluorouracil

Sasada,Shinsuke; Miyata,Yoshihiro; Tsutani,Yasuhiro; Tsuyama,Naohiro; Masujima,Tsutomu; Hihara,Jun; Okada,Morihito

doi:10.3892/or.2012.2182

Metabolomic analysis of dynamic response and drug resistance of gastric cancer cells to 5-fluorouracil

Authors:
- Shinsuke Sasada
- Yoshihiro Miyata
- Yasuhiro Tsutani
- Naohiro Tsuyama
- Tsutomu Masujima
- Jun Hihara
- Morihito Okada
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Affiliations: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan, Analytical Molecular Medicine and Devices Laboratory, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
Published online on: December 11, 2012 https://doi.org/10.3892/or.2012.2182
Pages: 925-931
Copyright: © Sasada et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

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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