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

Abstract

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.

Inhibition of apoptosis in Bacteroides fragilis enterotoxin‐stimulated intestinal epithelial cells through the induction of c‐IAP‐2

“…Therefore, it is possible that these two proinflammatory mediators may influence the epithelial cell death processes in response to BFT stimulation. This hypothesis may be supported by several studies that showed increased COX-2 activity and PGE 2 production by several stimulators, thereby inhibiting the apoptosis of gastrointestinal epithelial cells [22][23][24][25]. In the studies reported here, we have tested this hypothesis and have identified a mechanism for the antiapoptotic effects of cellular inhibitor of apoptosis protein-2 (c-IAP2) through the COX-2 and PGE 2 pathway in BFT-stimulated IEC.…”

Gnotobiotic IL-10−/−;NF-κBEGFP Mice Reveal the Critical Role of TLR/NF-κB Signaling in Commensal Bacteria-Induced Colitis

“…These studies illustrate that TLR signaling, apart from its proinflammatory effects, can have protective functions, which are missing in MyD88 Ϫ/Ϫ animals and thus render the host more susceptible to intestinal injury. A similar bipartite effect can be seen in cyclooxygenase-2, which is induced rapidly following intestinal injury and participates in mucosal inflammation, restitution, and protection (35,59,60).…”

The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells

“…Treatment of HCA-7 cells with PGE1-OH, a selective EP4 agonist [26], induced ERK phosphorylation. However, treatment with 17-phenyltrinor PGE 2 (2.1 μM), an (EP1/EP3 agonist) [26] did not induce ERK phosphorylation ( Fig. 2A).…”