Prostaglandin E ₂ Promotes Colon Cancer Cell Growth Through a G _s -Axin-ß-Catenin Signaling Axis

Abstract

How cyclooxygenase-2 (COX-2) and its proinflammatory metabolite prostaglandin E2 (PGE2) enhance colon cancer progression remains poorly understood. We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt by free G protein betagamma subunits and the direct association of the G protein alphas subunit with the regulator of G protein signaling (RGS) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. These findings may provide a molecular framework for the future evaluation of chemopreventive strategies for colorectal cancer.

Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells

“…The stabilization of E-cadherin/b-catenin at the cell-cell borders by MAGI1 overexpression and its loss from cell-cell borders following MAGI1 silencing is consistent with the model that MAGI1 suppresses Wnt/b-catenin signaling by decreasing the pool of free b-catenin. This model is also supported by the published evidence that the COX-2 main product, PGE 2 , leads to the inactivation of glycogen synthase kinase-3b, release of b-catenin from the axin/APC complex and its translocation to the nucleus, resulting in the activation of TFC/LEF1-dependent transcription (Castellone et al, 2005;Shao et al, 2005). As tumor cell exposure to PGE 2 results in MAGI1 reduction, it is conceivable that inflammatory and cancer conditions associated PGE 2 production, as it occurs in cancer, may cause a reduction of MAGI1 expression resulting in facilitated Wnt/b-catenin signaling.…”

“…kinase-3b (Castellone et al, 2005;Buchanan and DuBois, 2006). Consistent with such a mechanisms, COX-2 inhibition by celecoxib reduced polyp formation (Swamy et al, 2006).…”

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

“…However, exactly which receptor subtype plays a role in human colon carcinogenesis is only now becoming clear. Although recent studies suggest a role for the EP2 receptor in PGE 2 -induced cellular response, a caveat with these studies is the use of cell culture systems in which the EP2 receptor is ectopically expressed [40]. Our studies, which are in agreement with several other reports [36], indicate an important role for the EP4 receptor for the following reasons: 1) PGE1-OH (relatively selective EP4 agonist), but not 17-phenyltrinor PGE 2 (EP1/EP3 agonist) induced ERK phosphorylation; 2) pretreatment of HCA-7 cells with AH6809 (EP1/EP2 antagonist) did not have any effect on PGE 2 -induced ERK phosphorylation; 3) L-161,982 at concentrations that does not bind to either EP1 or EP2 receptors [18] abrogated PGE 2 -induced ERK phosphorylation.…”

Translational approaches to addressing complex genetic pathways in colorectal cancer

“…Activation of EP receptors leads to an array of downstream events, including activation of the epidermal growth factor receptor (EGFR), activation of the phosphatidyl-3-kinase (PI3K) and Akt pathways, which together result in the release of glycogen synthase kinase 3β from its stable complex with axin and β-catenin (7). Inactivation of glycogen synthase kinase 3β stabilizes β-catenin and permits its nuclear translocation, which in turn results in growth stimulation through transcriptional activation of TCF/LEF family members (7). There is additional complexity however, since PGE2 signaling through EP2 and EP4 leads to a feed-forward loop in which PGE2 itself stimulates cox-2 expression and thereby further enhances prostaglandin production (8,9).…”