Abstract 3665: Suppression of 15-Hydroxyprostaglandin Dehydrogenase in Helicobacter pylori-infected rt gastric mucosa cells and its restoration by curcumin.

Abstract

Abstract Helicobacter pylori (H. pylori) have been known to cause gastritis and promote gastric cancer development. H.pylori infection causes overproduction of prostaglandin E2 (PGE2), which has been implicated in inflammation and carcinogenesis. The intracellular level of PGE2 is regulated not only by its biosynthesis, but also by degradation. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyzes the first step of PGE2 degradation. In the present study, we have observed that H. pylori suppressed the expression of 15-PGDH in rat gastric mucosa (RGM)-1 cells. By using deletion constructs of 15-PGDH promoter, we found that the Ets-binding site is the most essential determinant of 15-PGDH expression in RGM-1 cells. H. pylori infection suppressed the phosphorylation of Elk-1, a major transcription factor of the Ets family. Notably, curcumin, a yellow coloring agent present in the rhizome of Curcuma longa Linn (Zingiberaceae) with anti-inflammatory activity, induced expression of 15-PGDH in RGM-1 cells. We have found that activator protein-1 (AP-1) is the most critical transcription factor responsible for curcumin-induced upregulation of 15-PGDH expression. Curcumin enhanced the expression of c-Jun and c-Fos, which are functional subunits of AP-1, in the nuclear fraction of RGM-1 cells. Knockdown of c-jun abrogated curcumin-induced expression of 15-PGDH. Curcumin induced phosphorylation of extracellular signal-regulated kinase (ERK1/2) and c-Jun NH2-terminal kinase (JNK1/2), but did not affect the phosphorylation of p38 mitogen-activated protein kinase (MAPK) in RGM-1 cells. Pharmacologic inhibition of each of above kinases abolished the curcumin-induced expression of c-Jun and 15-PGDH in RGM-1 cells. In another study, tetrahydrocurcumin which lacks the α,β-unsaturated carbonyl group failed to upregulate the expression 15-PGDH, suggesting that the electrophilic carbonyl moiety of curcumin plays a critical role in its induction of 15-PGDH expression in RGM-1 cells. Moreover, oral administration of curcumin increased the expression of 15-PGDH in the total protein lysate and enhanced the expression of c-Jun, c-Fos and CREB in the nuclear fraction of the mouse stomach. Curcumin again induced phosphorylation of ERK1/2 and JNK1/2, but did not affect that of p38 MAPK in the mouse stomach in vivo. Taken together, our study suggests that down-regulation of 15-PGDH expression induced by H. pylori infection may contribute, at least in part, to development of gastritis and gastric cancer, and upregulation of 15-PGDH expression by curcumin can account for the chemopreventive effect of this phytochemical on inflammation-associated gastric carcinogenesis. Citation Format: Ye-Sung Oh, Jeong-hwa Woo, Ji-Hye Jang, Young Wook Lee, Jong-Min Park, Young-Joon Surh, Hye-Kyung Na. Suppression of 15-Hydroxyprostaglandin Dehydrogenase in Helicobacter pylori-infected rt gastric mucosa cells and its restoration by curcumin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3665. doi:10.1158/1538-7445.AM2013-3665