EP4 mediates PGE2 dependent cell survival through the PI3 kinase/AKT pathway

被引:63
作者
George, Robert J.
Sturmoski, Mark A.
Anant, Shrikant
Houchen, Courtney W.
机构
[1] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA
[2] Univ Oklahoma, Hlth Sci Ctr, Div Digest Dis & Nutr, Dept Med, St Louis, MO 63110 USA
关键词
prostaglandin; EP4; receptor; apoptosis; survival; PI3; kinase;
D O I
10.1016/j.prostaglandins.2006.10.005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The anti-apoptotic effect of PGE(2) was examined in Jurkat cells (human T-cell leukemia) by incubation with PGE(2) (5 nM) prior to treatment with the cancer chemotherapeutic agent camptothecin. Apoptosis was evaluated by caspase-3 activity in cell extracts and flow cytometry of propidium iodide-labeled cells. Pre-incubation with PGE(2) reduced camptothecin-induced caspase activity by 30% and apoptosis by 35%, respectively. Pharmacological data demonstrate that the EP4 receptor is responsible for mediating the protection from camptothecin-induced apoptosis. Pre-treatment of the cells with the EP4 antagonist (EP4A) prior to PGE2 and camptothecin abolished the increased survival effect of PGE(2). Specific inhibition of the downstream of PI3 kinase or AKT/protein kinase but not protein kinase A prevents the observed increase in cell survival elicited by PGE(2). These findings have critical implications regarding the mechanism and potential application of PGE(2) receptor specific inhibition in cancer therapy. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:112 / 120
页数:9
相关论文
共 31 条
[1]   Exclusive expression of the Gs-linked prostaglandin E(2) receptor subtype 4 mRNA in human mononuclear Jurkat and KM-3 cells and coexpression of subtype 4 and 2 mRNA in U-937 cells [J].
Blaschke, V ;
Jungermann, K ;
Puschel, GP .
FEBS LETTERS, 1996, 394 (01) :39-43
[2]   G protein-coupled prostanoid receptors and the kidney [J].
Bryer, MD ;
Breyer, RM .
ANNUAL REVIEW OF PHYSIOLOGY, 2001, 63 :579-605
[3]   Mitochondrial dysfunction and oxidative stress as determinants of cell death/survival in stroke [J].
Chan, PH .
ROLE OF THE MITOCHONDRIA IN HUMAN AGING AND DISEASE: FROM GENES TO CELL SIGNALING, 2005, 1042 :203-209
[4]  
COLEMAN RA, 1994, PHARMACOL REV, V46, P205
[5]   Pharmacological characterization of [3H]-prostaglandin E2 binding to the cloned human EP4 prostanoid receptor [J].
Davis, TL ;
Sharif, NA .
BRITISH JOURNAL OF PHARMACOLOGY, 2000, 130 (08) :1919-1926
[6]  
DEVRIES GW, 1995, BRIT J PHARMACOL, V115, P1231
[7]   Phosphorylation of glycogen synthase kinase-3 and stimulation of T-cell factor signaling following activation of EP2 and EP4 prostanoid receptors by prostaglandin E2 [J].
Fujino, H ;
West, KA ;
Regan, JW .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (04) :2614-2619
[8]   Mechanism of prostaglandin (PG)E2-induced prolactin expression in human T cells:: Cooperation of two PGE2 receptor subtypes, E-prostanoid (EP) 3 and EP4, via calcium- and cyclic adenosine 5′-monophosphate-mediated signaling pathways [J].
Gerlo, S ;
Verdood, P ;
Gellersen, B ;
Hooghe-Peters, EL ;
Kooijman, R .
JOURNAL OF IMMUNOLOGY, 2004, 173 (10) :5952-5962
[9]   Prostaglandin E2 protects gastric mucosal cells from apoptosis via EP2 and EP4 receptor activation [J].
Hoshino, T ;
Tsutsumi, S ;
Tomisato, W ;
Hwang, HJ ;
Tsuchiya, T ;
Mizushima, T .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (15) :12752-12758
[10]   Disruption of cyclooxygenase-1 gene results in an impaired response to radiation injury [J].
Houchen, CW ;
Stenson, WF ;
Cohn, SM .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2000, 279 (05) :G858-G865