Prosurvival and antiapoptotic effects of PGE<sub>2</sub>in radiation injury are mediated by EP<sub>2</sub>receptor in intestine

Houchen, Courtney W.; Sturmoski, Mark; Anant, Shrikant; Breyer, Richard M.; Stenson, William F.

doi:10.1152/ajpgi.00240.2002

Cited by 64 publications

(61 citation statements)

References 55 publications

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“…Deficiency of PGE 2 in the lungs of patients with IPF has important profibrotic consequences (4,8). PGE 2 has been shown outside the lung to play an important role in regulating the sensitivity of different cell types to apoptotic stimuli (23,24). A recent study by Huang and colleagues demonstrates that PGE 2 induces fibroblast apoptosis and enhances the fibrotic response of fibroblasts to a combination of FasL and cycloheximide (35).…”

Section: Discussionmentioning

confidence: 99%

“…COX-2 overexpression plays an important part in the development of a range of epithelial-derived tumors through inhibition of epithelial apoptosis (23). In a murine model of radiationinduced gastric epithelial injury, exogenous PGE 2 protects epithelial cells from apoptosis (24). In contrast, apoptosis of both human synovial fibroblasts and colonic fibroblasts is promoted by PGE 2 (25,26).…”

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confidence: 99%

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Diminished Prostaglandin E₂Contributes to the Apoptosis Paradox in Idiopathic Pulmonary Fibrosis

Maher¹,

Evans²,

Bottoms³

et al. 2010

Am J Respir Crit Care Med

170

161

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Rationale: Patients with idiopathic pulmonary fibrosis (IPF), a progressive disease with a dismal prognosis, exhibit an unexplained disparity of increased alveolar epithelial cell (AEC) apoptosis but reduced fibroblast apoptosis. Objectives: To examine whether the failure of patients with IPF to upregulate cyclooxygenase (COX)-2, and thus the antifibrotic mediator prostaglandin (PG)E 2 , accounts for this imbalance. Methods: Fibroblasts and primary type II AECs were isolated from control and fibrotic human lung tissue. The effects of COX-2 inhibition and exogenous PGE 2 on fibroblast and AEC sensitivity to Fas ligand (FasL)-induced apoptosis were assessed. Measurements and Main Results: IPF lung fibroblasts are resistant to FasL-induced apoptosis compared with control lung fibroblasts. Inhibition of COX-2 in control lung fibroblasts resulted in an apoptosis-resistant phenotype. Administration of PGE 2 almost doubled the rate of FasL-induced apoptosis in fibrotic lung fibroblasts compared with FasL alone. Conversely, in primary fibrotic lung type II AECs, PGE 2 protected against FasL-induced apoptosis. In human control and, to a greater extent, fibrotic lung fibroblasts, PGE 2 inhibits the phosphorylation of Akt, suggesting that regulation of this prosurvival protein kinase is an important mechanism by which PGE 2 modulates cellular apoptotic responses. Conclusions: The observation that PGE 2 deficiency results in increased AEC but reduced fibroblast sensitivity to apoptosis provides a novel pathogenic insight into the mechanisms driving persistent fibroproliferation in IPF.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Diminished Prostaglandin E₂Contributes to the Apoptosis Paradox in Idiopathic Pulmonary Fibrosis

Maher¹,

Evans²,

Bottoms³

et al. 2010

Am J Respir Crit Care Med

170

161

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“…COX-1-derived PGE 2 was recently demonstrated to promote crypt cell survival and protect the gastrointestinal epithelium from radiation-induced apoptosis via EP2. Crypt cell apoptosis was increased dramatically in the jejunum of EP2 Ϫ/Ϫ mice after irradiation compared with wild-type mice (34,35). PGE 2 has also been demonstrated to increase the expression of the antiapoptotic protein Bcl-2 in vitro (36).…”

Section: Discussionmentioning

confidence: 99%

Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland

Chandrasekharan

Foley

Jania

et al. 2005

Journal of Lipid Research

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The mammary gland, like most tissues, produces measurable amounts of prostaglandin E 2 (PGE 2 ), a metabolite of arachidonic acid produced by sequential actions of two cyclooxygenases (COX-1 and COX-2) and three terminal PGE synthases: microsomal prostaglandin E 2 synthase-1 (mPGES1), mPGES2, and cytosolic prostaglandin E 2 synthase (cPGES). High PGE 2 levels and COX-2 overexpression are frequently detected in mammary tumors and cell lines. However, less is known about PGE 2 metabolic enzymes in the context of normal mammary development. Additionally, the primary COX partnerships of terminal PGE synthases and their contribution to normal mammary PGE 2 biosynthesis are poorly understood. We demonstrate that expression of COX-1, generally considered constitutive, increases dramatically with lactogenic differentiation of the murine mammary gland. Concordantly, total PGE 2 levels increase throughout mammary development, with highest levels measured in lactating tissue and breast milk. In contrast, COX-2 expression is extremely low, with only a modest increase detected during mammary involution. Expression of the G s -coupled PGE 2 receptors, EP2 and EP4, is also temporally regulated, with highest levels detected at stages of maximal proliferation. PGE 2 production is dependent on COX-1, as PGE 2 levels are nearly undetectable in COX-1 -deficient mammary glands. Interestingly, PGE 2 levels are similarly reduced in lactating glands of mPGES1 -deficient mice, indicating that PGE 2 biosynthesis results from the coordinated activity of COX-1 and mPGES1. We thus provide evidence for the first time of functional coupling between COX-1 and mPGES1 in the murine mammary gland in vivo.

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“…Prostaglandin E 2 (PGE 2 ) is radioprotective for intestinal epithelium; that is, administration of 16,16-dimethyl PGE 2 (dmPGE 2 ), a stable analog of PGE 2 , prior to radiation increases the number of surviving crypts after radiation (6,7). The increased crypt survival seen with PGE 2 signaling correlates with diminished radiation-induced apoptosis (8,9). The radioprotective effects of PGE 2 have practical consequences for radiation therapy (reviewed in refs.…”

Section: Introductionmentioning

confidence: 99%

“…19). EP 2 mediates the reduction of apoptosis and the enhancement of crypt survival observed in the intestine of dmPGE 2 -treated irradiated mice (9). One possible signaling pathway for the effects of PGE 2 on apoptosis is the phosphorylation of AKT, a ubiquitously expressed serine/threonine kinase that is downstream of PI3K (reviewed in ref.…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E2 reduces radiation-induced epithelial apoptosis through a mechanism involving AKT activation and bax translocation

Tessner¹,

Muhale²,

Riehl³

et al. 2004

J. Clin. Invest.

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Prostaglandin E 2 (PGE 2 ) synthesis modulates the response to radiation injury in the mouse intestinal epithelium through effects on crypt survival and apoptosis; however, the downstream signaling events have not been elucidated. WT mice receiving 16,16-dimethyl PGE 2 (dmPGE 2 ) had fewer apoptotic cells per crypt than untreated mice. Apoptosis in Bax -/-mice receiving 12 Gy was approximately 50% less than in WT mice, and the ability of dmPGE 2 to attenuate apoptosis was lost in Bax -/-mice. Positional analysis revealed that apoptosis in the Bax -/-mice was diminished only in the bax-expressing cells of the lower crypts and that in WT mice, dmPGE 2 decreased apoptosis only in the bax-expressing cells. The HCT-116 intestinal cell line and Bax -/-HCT-116 recapitulated the apoptotic response of the mouse small intestine with regard to irradiation and dmPGE 2 . Irradiation of HCT-116 cells resulted in phosphorylation of AKT that was enhanced by dmPGE 2 through transactivation of the EGFR. Inhibition of AKT phosphorylation prevented the reduction of apoptosis by dmPGE 2 following radiation. Transfection of HCT-116 cells with a constitutively active AKT reduced apoptosis in irradiated cells to the same extent as in nontransfected cells treated with dmPGE 2 . Treatment with dmPGE 2 did not alter bax or bcl-x expression but suppressed bax translocation to the mitochondrial membrane. Our in vivo studies indicate that there are bax-dependent and bax-independent radiation-induced apoptosis in the intestine but that only the bax-dependent apoptosis is reduced by dmPGE 2 . The in vitro studies indicate that dmPGE 2 , most likely by signaling through the E prostaglandin receptor EP 2 , reduces radiation-induced apoptosis through transactivation of the EGFR and enhanced activation of AKT and that this results in reduced bax translocation to the mitochondria.

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Prosurvival and antiapoptotic effects of PGE₂in radiation injury are mediated by EP₂receptor in intestine

Cited by 64 publications

References 55 publications

Diminished Prostaglandin E₂Contributes to the Apoptosis Paradox in Idiopathic Pulmonary Fibrosis

Diminished Prostaglandin E₂Contributes to the Apoptosis Paradox in Idiopathic Pulmonary Fibrosis

Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland

Prostaglandin E2 reduces radiation-induced epithelial apoptosis through a mechanism involving AKT activation and bax translocation

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Prosurvival and antiapoptotic effects of PGE2in radiation injury are mediated by EP2receptor in intestine

Cited by 64 publications

References 55 publications

Diminished Prostaglandin E2Contributes to the Apoptosis Paradox in Idiopathic Pulmonary Fibrosis

Diminished Prostaglandin E2Contributes to the Apoptosis Paradox in Idiopathic Pulmonary Fibrosis

Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland

Prostaglandin E2 reduces radiation-induced epithelial apoptosis through a mechanism involving AKT activation and bax translocation

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Prosurvival and antiapoptotic effects of PGE₂in radiation injury are mediated by EP₂receptor in intestine

Diminished Prostaglandin E₂Contributes to the Apoptosis Paradox in Idiopathic Pulmonary Fibrosis

Diminished Prostaglandin E₂Contributes to the Apoptosis Paradox in Idiopathic Pulmonary Fibrosis