DA6034 promotes gastric epithelial cell migration and wound-healing through the mTOR pathway

• Published in: Journal of gastroenterology and hepatology Vol. 27; no. 2; pp. 397 - 405
• Main Authors: Kim, Young Woo, Lee, Woo Hyung, Choi, Seul Min, Seo, Yoon Young, Ahn, Byoung Ok, Kim, Soon Hoe, Kim, Sang Geon
• Format: Journal Article
• Language: English
• Published: Melbourne, Australia Blackwell Publishing Asia 01-02-2012
• Subjects: Anti-Ulcer Agents - pharmacology; Cell Line; Cell Movement - drug effects; Cell Proliferation - drug effects; DA6034; Dose-Response Relationship, Drug; Enzyme Activation; Epithelial Cells - drug effects; Epithelial Cells - enzymology; Epithelial Cells - pathology; Extracellular Signal-Regulated MAP Kinases - metabolism; Flavonoids - pharmacology; Gastric Mucosa - drug effects; Gastric Mucosa - enzymology; Gastric Mucosa - pathology; Humans; migration; mTOR; Phosphatidylinositol 3-Kinase - metabolism; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; S6K1; Signal Transduction - drug effects; Time Factors; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; wound healing; Wound Healing - drug effects
• ISSN: 0815-9319; 1440-1746
• DOI: 10.1111/j.1440-1746.2011.06873.x

Background and Aim:  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.