Microsomal prostaglandin E synthase-1 inhibition blocks proliferation and enhances apoptosis in oesophageal adenocarcinoma cells without affecting endothelial prostacyclin production

Beales, Ian L P and Ogunwobi, Olorunseun O (2010) Microsomal prostaglandin E synthase-1 inhibition blocks proliferation and enhances apoptosis in oesophageal adenocarcinoma cells without affecting endothelial prostacyclin production. International Journal of Cancer, 126 (9). pp. 2247-2255. ISSN 1097-0215

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Abstract

Prostaglandins are important in the progression of various gastrointestinal cancers including oesophageal adenocarcinoma (OAC). Cyclo-oxygenase (COX)-2 inhibitors reduce OAC prostaglandin production but also have potentially detrimental effects on vascular endothelial function by reducing prostacyclin production and increasing the risk of cardiovascular events. We have examined the effects of inhibiting microsomal prostaglandin synthase-1 (mPGES-1), the enzyme downstream of COX-2 in the prostaglandin synthetic cascade. In OAC cells, reduction of mPGES-1 with RNA interference blocked PGE2 production, inhibited serum-induced proliferation and enhanced apoptosis in the COX-2 expressing cell lines (OE33 and FLO) but had no effect in COX-2 deficient BIC-1 cells. Three different methods of inhibiting mPGES-1 (RNA interference, a novel small molecule inhibitor and the endogenous inhibitor 15-deoxy-Delta(12,14)-PGJ(2)) also blocked leptin induced mPGES-1 expression and PGE2 production and abolished the leptin-induced proliferative and anti-apoptotic effects in OE33 cells, without affecting COX-2 expression. The anti-proliferative effects were equivalent to those produced by COX-2 inhibitory concentrations of celecoxib and NS-398. However, unlike the two COX-2 inhibitors, mPGES-1 inhibition did not reduce endothelial prostacyclin production. In contrast to the effects of the COX-2 inhibitor celecoxib, mPGES-1 inhibition had no effects on Akt kinase activity in OAC cells. We conclude that inhibition of mPGES-1 has potentially beneficial effects in OAC without the potentially detrimental effects on vascular endothelial prostacyclin synthesis. We have also confirmed that celecoxib has anticancer actions separate from the inhibition of COX-2. Inhibition of mPGES-1 may be therapeutically useful in the treatment and prevention of OAC.

Item Type: Article
Uncontrolled Keywords: adenocarcinoma,apoptosis,cell line, tumor,cell proliferation,cell survival,endothelial cells,epoprostenol,esophageal neoplasms,humans,intramolecular oxidoreductases,leptin,pyrazoles,rna, small interfering,sulfonamides
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
University of East Anglia > Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
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Depositing User: EPrints Services
Date Deposited: 25 Nov 2010 11:12
Last Modified: 25 Jul 2018 04:16
URI: https://ueaeprints.uea.ac.uk/id/eprint/14501
DOI: 10.1002/ijc.24875

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