E-type prostanoid receptor 4 (EP4) in disease and therapy

Abstract

The large variety of biological functions governed by prostaglandin (PG) E2 is mediated by signaling through four distinct E-type prostanoid (EP) receptors. The availability of mouse strains with genetic ablation of each EP receptor subtype and the development of selective EP agonists and antagonists have tremendously advanced our understanding of PGE2 as a physiologically and clinically relevant mediator. Moreover, studies using disease models revealed numerous conditions in which distinct EP receptors might be exploited therapeutically. In this context, the EP4 receptor is currently emerging as most versatile and promising among PGE2 receptors. Anti-inflammatory, anti-thrombotic and vasoprotective effects have been proposed for the EP4 receptor, along with its recently described unfavorable tumor-promoting and pro-angiogenic roles. A possible explanation for the diverse biological functions of EP4 might be the multiple signaling pathways switched on upon EP4 activation. The present review attempts to summarize the EP4 receptor-triggered signaling modules and the possible therapeutic applications of EP4-selective agonists and antagonists.

COX-2 induces lytic reactivation of EBV through PGE2 by modulating the EP receptor signaling pathway

“…This supports the hypothesis that among all four EP receptors, EP4 may prove to be the most versatile and important receptor. EP4 is widely known for its cancer promoting and pro-angiogenic activities (Konya et al, 2013). It is important to note that these receptors did not get upregulated in response to LPS treatment in EBV negative Burkitt’s Lymphoma cells.…”

Platelets and cancer: a casual or causal relationship: revisited

“…Since PGE 2 and its enzymatic metabolite 13,14-dihydro-15-ketoPGE 2 prevent PGI 2 inhibition of TCIPA, this underscores the need for selective targeting of the PGE 2 pathway [63, 446]. Although attempts have been made to selectively target the PGE2 pathway, more effective agents are needed [530, 531]. These new drugs could be used in conjunction with low-dose aspirin to eliminate the genesis and spread of many different cancers.…”

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

“…Each EP receptor subtype possesses homeostatic and pathophysiological properties [12]. EP4, for example, mediates the pro-inflammatory and hyperalgesic effects of PGE 2 in distinct inflammatory diseases (e.g., arthritis) and promotes carcinogenesis and tumor progression.…”

“…EP4, for example, mediates the pro-inflammatory and hyperalgesic effects of PGE 2 in distinct inflammatory diseases (e.g., arthritis) and promotes carcinogenesis and tumor progression. On the other hand, EP4 essentially contributes to the anti-inflammatory actions of PGE 2 , possesses broncho-, vaso-and cardioprotective effects, contributes to wound healing and tissue repair and is critically involved in renal homeostasis and kidney development [12]. This dualism of EP receptors makes the requirement for either EP4 receptor agonists and antagonists a matter of the respective disease and raises safety concerns, even so EP4 receptor ligands might reveal superior to COX inhibitors.…”