Hepatocyte growth factor protects gastric epithelial cells against ceramide-induced apoptosis through induction of cyclooxygenase-2

Forced overexpression of cyclooxygenase-2 (COX-2) in intestinal cells has b een shown to be associated with resistance to apoptosis. However, the role of physiologically-induced COX-2 in the regulation of apoptosis remains unc lear. In the present study, we examined whether hepatocyte growth factor (H GF)-induced COX-2 affects ceramide-induced apoptosis in RGM-1 gastric epith elial cells. An externally applied cell permeable ceramide analogue, C-2-ce ramide, caused RGM-1 cell death in a dose-dependent manner, whereas an inac tive ceramide analogue, C-2-dihydroceramide, did not. TdT-mediated dUTP nic k end labeling (TUNEL) assay showed that the C-2-cersunide-induced cell dea th was apoptosis. Application of HGF rapidly induced the expression of COX- 2, and HGF prevented the apoptotic cell death induced by C-2-ceramide. Howe ver, the anti-apoptotic action of HGF was antagonized by coapplication of N S-398, a selective inhibitor of COX-2. Thus, these results indicate that CO X-2 is involved in the survival signaling from HGF in gastric epithelial ce lls, and suggest a role for physiologically-induced COX-2 in the protection of the cells from apoptosis. (C) 2000 Elsevier Science Inc. All rights res erved.