Prostaglandin E2 receptor 2 (EP2) and Prostaglandin E2 receptor 4 (EP4) (EP2/EP4)

The Prostaglandin E2 receptor 2 (EP2) and Prostaglandin E2 receptor 4 (EP4) are G protein-coupled receptors that serve as the primary mediators for the biological actions of Prostaglandin E2 (PGE2) [1]. Both receptors are predominantly coupled to Gs proteins, which activate adenylate cyclase to increase intracellular cAMP levels, although EP4 also exhibits signaling through Gi and PI3K pathways [2]. In the context of oncology, the PGE2-EP2/EP4 axis is a critical driver of immune evasion, as it suppresses the activation of T cells and natural killer cells while promoting the activity of immunosuppressive cells like myeloid-derived suppressor cells [3, 5]. Dual antagonism of these receptors is currently being explored in clinical trials to overcome this immunosuppression and enhance the efficacy of cancer immunotherapies [4]. Beyond their role in cancer, EP2 and EP4 are involved in diverse physiological processes including bone remodeling, vascular tone regulation, and the maintenance of the gastrointestinal mucosal barrier [1, 2]. Consequently, targeting these receptors requires careful management of potential side effects related to renal function and gastrointestinal health [5].

Other names

PTGER2PTGER4Prostanoid EP2 receptorProstanoid EP4 receptorPGE2 receptor subtypes 2 and 4PGE receptor EP2PGE receptor EP4

Dual antagonism of the EP2 and EP4 receptors inhibits the binding of Prostaglandin E2 (PGE2), thereby preventing the activation of the Gs-adenylate cyclase-cAMP signaling pathway. In oncology, this mechanism reverses PGE2-mediated immunosuppression in the tumor microenvironment, enhancing the activity of cytotoxic T cells and natural killer cells [4, 5]. In other contexts, agonists of these receptors are used to induce vasodilation or promote bone healing [1].