The EP4 antagonist, L-161,982, induces apoptosis, cell cycle arrest, and inhibits prostaglandin E2-induced proliferation in oral squamous carcinoma Tca8113 cells

Background: Recent studies suggest that cyclooxygenase 2 (COX-2) inhibitors may enhance the toxic effects of Anticancer drugs on tumor cells, including oral squamous cell carcinoma (OSCC), but its long-term use can cause side effects such as stomach ulcers and myocardial infarction. Our aim was to investigate proliferative effects of a downstream product of COX-2, prostaglandin E2 (PGE2), in human oral squamous carcinoma cell line Tca8113 and explore the effects of PGE2 receptors, especially EP4 receptor, on the growth of Tca8113 cells.

Methods: To evaluate the effects of PGE2 and EP receptors on Tca8113 cells, CCK8 assay, Western blotting, cell cycle analysis, and Apoptosis assay were performed.

Results: We found that the EP4 receptor agonist, PGE1-OH, could mimick PGE2 rescued the inhibitory effect of celecoxib and induced cell growth via ERK phosphorylation, and the EP4 receptor antagonist, L-161,982, completely blocked PGE2-stimulated ERK phosphorylation and proliferation of Tca8113 cells. Furthermore, L-161,982 may induce Apoptosis and block cell cycle progression at s phase by upregulating Bax and p21 protein levels and by downregulating Bcl-2, CDK2, and cyclin A2 protein levels.

Conclusions: Our results indicate that EP4 receptor mediates PGE2-induced cell proliferation through ERK signaling, and inhibition of EP4 receptor may represent an alternative therapeutic strategy for the prevention and treatment of OSCC.