EP4 mediates PGE2 dependent cell survival through the PI3 kinase/AKT pathway

The anti-apoptotic effect of PGE2 was examined in Jurkat cells (human T-cell leukemia) by incubation with PGE2 (5 nM) prior to treatment with the cancer chemotherapeutic agent camptothecin. Apoptosis was evaluated by caspase-3 activity in cell extracts and flow cytometry of propidium iodide-labeled cells. Pre-incubation with PGE2 reduced camptothecin-induced caspase activity by 30% and apoptosis by 35%, respectively. Pharmacological data demonstrate that the EP4 receptor is responsible for mediating the protection from camptothecin-induced apoptosis. Pre-treatment of the cells with the EP4 antagonist (EP4A) prior to PGE2 and camptothecin abolished the increased survival effect of PGE2. Specific inhibition of the downstream of PI3 kinase or AKT/protein kinase but not protein kinase A prevents the observed increase in cell survival elicited by PGE2. These findings have critical implications regarding the mechanism and potential application of PGE2 receptor specific inhibition in cancer therapy.