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.

High COX‐2 expression in cancer‐associated fibiroblasts contributes to poor survival and promotes migration and invasiveness in nasopharyngeal carcinoma

“…COX‐2, an enzyme that catalyzes the formation of prostaglandins, affects tumor cell proliferation and host immune response and is undetectable in most of the normal tissue. Evidence from clinical and preclinical studies indicates that COX‐2‐derived prostaglandins participate in carcinogenesis, suppression of host immunity, apoptosis inhibition, angiogenesis, and tumor cell invasiveness and metastasis . Our previous studies showed that a high expression of COX‐2 is associated with the recurrence and a poor prognosis of patients with NPC, and COX‐2 may play a critical role in chemotherapeutic resistance in NPC via the inhibition of chemotherapy‐induced senescence via the inactivation of p53 .…”

Mesenchymal Cells in Colon Cancer

“…95,[98][99][100] Expression of COX-2 specifically in IMCs protects mice from tissue damage and mucosal repair caused by irradiation, DSS administration, or biopsy injury. 25,101,102 Expression of COX-2 by IMCs is regulated by cytokines (such as TNF and IL-1), microbial products (such as lipoproteins), and growth factors (such as insulin-like growth factor 2 messenger RNA binding protein 1 [IGF2BP1] and FGF9). [25][26][27]103,104 Interestingly, mesenchymal stem cells in the lamina propria express the highest levels of COX-2 and localize to sites of injury where they reposition themselves to mediate tissue repair via MYD88 signaling.…”

Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury

“…Together, they play a vital role in the production of prostaglandins that can have both growth-stimulatory and antiapoptotic effects (25). Ptgs1 and -2 have also been shown to play a significant role in protection of the intestine from both irradiation and DSS-mediated damage (24,26,27), primarily though the production of PGE 2 . Recently PGE 2 was shown to transactivate the canonical Wnt signaling pathway (28).…”