W1709 Role of RHOA GTPase and Its Effectors Rho-Coiled Coiled Kinase (ROCK) and Diaphanous (Mdia) in Modulation of Deformation-Induced MAPK Motogenic Signals in Human CACO-2 Intestinal Epithelial Cells

Abstract

G A A b st ra ct s with a low dose of indomethacin, orally administered rebamipide suppressed celecoxibinduced mucosal apoptosis and lesion production but did not decrease PGE2 levels in the stomach. Rebamipide also suppressed celecoxib-induced increases in [Ca2+]i, the ER stress response, mitochondrial dysfunction and apoptosis In Vitro. Rebamipide did not suppress increases in [Ca2+]i, ER stress response and apoptosis induced by thapsigargin and ionomycin. We also found that rebamipide suppresses the increases in [Ca2+]i and ER stress response induced by an activator of voltage-dependent L-type Ca2+ channels and that another blocker of this channel suppresses celecoxib-induced increases in [Ca2+]i and ER stress response. Conclusions: These results suggest that celecoxib activates voltage-dependent L-type Ca2+ channels and that rebamipide blocks this activation, resulting in suppression of celecoxib-induced apoptosis. Although oral administration of celecoxib produces significant levels of gastric lesions in humans, especially upon long-term treatment or in patients coadministered with low doses of aspirin, it produces few gastric lesions in animals. We consider that celecoxib does not produce acute gastric lesions in animals due to its inability to decrease the gastric PGE2 level and that an accidental decrease in gastric PGE2 level or that induced by a low dose of aspirin causes the observed celecoxib-dependent production of gastric lesions in humans. Therefore, the observation that rebamipide suppresses celecoxibdependent production of gastric lesions in mice pre-administered with a low dose of indomethacin suggests that rebamipide would be clinically effective for the prevention of celecoxib-produced gastric lesions.