Cyclooxygenase-2-derived prostaglandin E2 protects mouse embryonic stem cells from apoptosis

被引:55
作者
Liou, Jun-Yang
Ellent, David P.
Lee, Sang
Goldsby, Jennifer
Ko, Bor-Sheng
Matijevic, Nena
Huang, Jaou-Chen
Wu, Kenneth K.
机构
[1] Univ Texas, Hlth Sci Ctr, Div Hematol, Houston, TX 77030 USA
[2] Univ Texas, Hlth Sci Ctr, Vasc Biol Res Ctr, Houston, TX 77030 USA
[3] Univ Texas, Hlth Sci Ctr, Dept Obstet & Gynecol, Houston, TX 77030 USA
[4] Natl Hlth Res Inst, Zhunan, Miaoli, Taiwan
关键词
mouse embryonic stem cell; cyclooxygenase-2; PGE(2); EP2; receptor; apoptosis; Akt;
D O I
10.1634/stemcells.2006-0505
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Little is known about prostaglandin synthesis and function in embryonic stem cells. We postulated that mouse embryonic stem (mES) cells possess enzymes to synthesize protective prostaglandins. Compared with differentiated adult cells, mES cells were less susceptible to H2O2-induced apoptosis. However, their apoptosis was enhanced by indomethacin or SC-236, a selective inhibitor of cyclooxygenase (COX)-2. Analysis of COX pathway enzymes by Western blotting revealed expression of COX-2 and cytosolic and microsomal prostaglandin E-2 (PGE(2)) synthases. COX-1 and prostacyclin (PGI(2)) synthases were undetectable. mES cells produced PGE(2) but not PGI(2). Importantly, PGE(2) rescued mES cells from apoptosis. To elucidate the signaling mechanism by which PGE(2) inhibits apoptosis, we analyzed E-type prostaglandin (EP) receptors by Western blots. All EP isoforms were detected except EP4. Butaprost, a specific EP2 agonist, rescued mES cells from apoptosis, whereas sulprostone, an EP1/EP3 agonist, had no effect, suggesting selective interaction of PGE(2) with EP2. The antiapoptotic effect of PGE(2) was abrogated by Ly-294002 or wortmannin but not H-89 or a specific inhibitor of protein kinase A, suggesting signaling via phosphatidylinositol-3 kinase (PI-3K). Akt was constitutively active in mES cells, which were inhibited by indomethacin and rescued by PGE(2). The rescuing effect of PGE(2) was abrogated by Ly-294002. These results indicate that mES cells constitutively express COX-2 and PGE synthases and produce PGE(2), which confers resistance to apoptosis via EP2-mediated activation of PI-3K to the Akt pathway.
引用
收藏
页码:1096 / 1103
页数:8
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