title: Metabolomic analysis of dynamic response and drug resistance of gastric             cancer cells to 5-fluorouracil.
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 meta-bolomic             approach, a result that was confirmed by conventional methods. In the future,             metabolomics will play an important role in the field of cancer research.
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation                     Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Sasada
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyata
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsutani
authors.forename: Naohiro
authors.initials: N
authors.lastname: Tsuyama
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masujima
authors.forename: Jun
authors.initials: J
authors.lastname: Hihara
authors.forename: Morihito
authors.initials: M
authors.lastname: Okada
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D055442:Metabolome / Q000187:drug effects*; D055432:Metabolomics; D011394:Proline Oxidase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy*; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000596:Amino Acids; D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D013481:Superoxides; D011394:Proline Oxidase; C582834:PRODH protein, human; D005472:Fluorouracil