title: DA6034 promotes gastric epithelial cell migration and wound-healing through the mTOR pathway.
abstract: OBJECTIVE
  7-Carboxymethyloxy-3',4',5-trimethoxy flavone (DA6034), a synthetic derivative of eupatilin, has a protective effect on gastric mucosa against various ulcerogens, and is currently in the phase III clinical trial in the treatment of peptic ulcer disease. Cell migration and/or growth plays a role in the repair process of gastric ulcer, so this study investigated the effect of DA6034 on the movement and proliferation of gastric epithelial cells and its associated signaling pathway.
  
  
  METHODS
  The migration of AGS or SNU484 human gastric epithelial cells was shown by scratch-induced wound healing and transwell assays, and the proliferation of the cells was assessed by FACS and proliferation assays.
  
  
  RESULTS
  Treatment of DA6034 promoted the migration of gastric epithelial cells in a concentration-dependent manner. DA6034 treatment facilitated the phosphorylation of mTOR that led to an increase in the activity of S6K1, indicating its ability to activate mTOR and S6K1. Rapamycin aborted the wound-healing effect of DA6034, which supported the role of mTOR activation in the wound-healing process. In addition, DA6034 treatment increased PI3K-dependent Akt phosphorylation, which was necessary for the enhancement of cell migration. DA6034, however, did not stimulate the proliferation of gastric epithelial cells, being consistent with no activation of ERK1/2 by the agent.
  
  
  CONCLUSIONS
  DA6034 has the ability to heal scratch wounds, which may result from an increase in gastric epithelial cell migration as mediated by PI3K-Akt-dependent activation of mTOR and S6K1. Our finding may be of help in understanding the molecular basis of the anti-ulcer effect of DA6034.
authors.affiliation: Innovative Drug Research Center for Metabolic and Inflammatory Diseases, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Young Woo
authors.initials: YW
authors.lastname: Kim
authors.forename: Woo Hyung
authors.initials: WH
authors.lastname: Lee
authors.forename: Seul Min
authors.initials: SM
authors.lastname: Choi
authors.forename: Yoon Young
authors.initials: YY
authors.lastname: Seo
authors.forename: Byoung Ok
authors.initials: BO
authors.lastname: Ahn
authors.forename: Soon Hoe
authors.initials: SH
authors.lastname: Kim
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
mesh_terms: D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000897:Anti-Ulcer Agents; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D048049:Extracellular Signal-Regulated MAP Kinases; C121889:recoflavone