Cyclooxygenase-2-Derived Prostaglandin E2 Protects Mouse Embryonic Stem Cells from Apoptosis

Abstract

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 H 2 O 2 -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.

Proliferation and Pluripotency of Human Embryonic Stem Cells Maintained on Type I Collagen

“…PGE 2 was found to have a positive affect on the growth of hematopoietic stem cell progenitors obtained from zebrafish and mouse embryonic stem cells [84]. PTGS2 activity and PGE 2 have also been associated with mouse embryonic stem cell proliferation [85][86][87] and prevention of apoptosis [88]. These data are in agreement with our findings of increased PTGS2 activity and PGE 2 secretion in cells that are supportive of hESC growth.…”

“…In this study, we also detected high expression of PGIS in cells that were supportive of hESC growth and found significantly higher concentrations of 6-k-PGF 1a in hESC supportive CM than in nonsupportive CM. In a study on mouse embryonic stem cells, however, no PGIS was detected in the cell lysate and no 6-k-PGF 1a was detected in the CM of undifferentiated cells [88]. Increased levels of PGI 2 have also recently been associated with inducing hESC to form cardiomyocytes [89], indicating varying roles for PGI 2 depending on the species and specific microenvironment.…”

Host knockout of E-prostanoid 2 receptors reduces tumor growth and causes major alterations of gene expression in prostaglandin E2-producing tumors

“…In the present study, several hundreds of genes showed changed expression in the tumor tissues from the EP2-knockout mice compared with tumor tissues from the wild-type mice. A reason for this could be that EP2 signaling in host tissues is involved in several different pathways that are important events in tumor cells associated with tumor progression, including angiogenesis, the upregulation of COX-2, the loss of E-cadherin expression and anti-apoptosis in stem cells (16,22,(25)(26)(27)(28). Prom-1, also known as CD133, and CD44 are well-known markers of cancer stem cells, indicating reduced gene expression in the tumor tissues from the EP2-knockout mice in the present study.…”

Vascular endothelial growth factor regulates germ cell survival during establishment of spermatogenesis in the bovine testis

“…Prostaglandin-endoperoxide synthase 2 (PTGS2) is critical for germ cell maturation and somatic-germ cell interactions in the mammalian gonad both in vivo and in vitro (Neal et al 1975, Takahashi et al 2006, Winnall et al 2007. Recent evidence suggests that this multifunctional enzyme is also responsible for protecting mouse embryonic stem cells and renal interstitial cells from oxidative stress and hypertonicity-induced apoptosis (Moeckel et al 2003, Liou et al 2007); thus, we evaluated the mRNA expression of PTGS2 in response to VEGF treatment. In respect to the 0-h time point, VEGF treatment significantly induced the expression of PTGS2 in bovine testis tissue at 3 h, 6 h (P!0.001), and 24 h (P!0.01) when compared with controls ( Fig.…”