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

Metabolomics has developed as an important new tool in cancer research.It is expected to lead to the discovery of biomarker candidates for cancer diagnosisand treatment. The current study aimed to perform a comprehensive metabolomicanalysis of the intracellular dynamic responses of human gastric cancer cellsto 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 measuredby liquid chromatography-mass spectrometry. Candidates for drug targets were selectedaccording 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-polymerasechain reaction. The number of metabolites in cancer cells dramatically changedduring short-term treatment with 5-FU. Particularly, proline was reduced to one-thirdof its original level and glutamate was increased by a factor of 3 after 3 h oftreatment. The metabolic production of glutamate from proline proceeds by prolinedehydrogenase (PRODH), producing superoxide. After 5-FU treatment, PRODH mRNAexpression was upregulated 2-fold and production of superoxide was increased bya factor of 3. In 5-FU-resistant cells, proline and glutamate levels were lessaffected than in non-resistant cells, and PRODH mRNA expression and superoxidegeneration were not increased following treatment. In conclusion, the authorsidentified a candidate biomarker, PRODH, for drug effects using a meta-bolomicapproach, a result that was confirmed by conventional methods. In the future,metabolomics will play an important role in the field of cancer research.