Role of Prostaglandin Receptor EP2 in the Regulations of Cancer Cell Proliferation, Invasion, and Inflammation

Abstract

Population studies, preclinical, and clinical trials suggest a role for cyclooxygenase-2 (COX-2, PTGS2) in tumor formation and progression. The downstream prostanoid receptor signaling pathways involved in tumorigenesis are poorly understood, although prostaglandin E2 (PGE 2 ), a major COX-2 metabolite which is usually upregulated in the involved tissues, presumably plays important roles in tumor biology. Taking advantage of our recently identified novel selective antagonist for the EP2 (PTGER2) subtype of PGE 2 receptor, we demonstrated that EP2 receptor activation could promote prostate cancer cell growth and invasion in vitro, accompanied by upregulation of the tumor-promoting inflammatory cytokines, such as IL-1b and IL-6. Our results suggest the involvement of prostaglandin receptor EP2 in cancer cell proliferation and invasion possibly via its inflammatory actions, and indicate that selective blockade of the PGE 2 -EP2 signaling pathway via small molecule antagonists might represent a novel therapy for tumorigenesis.

EP2 Receptor Signaling Pathways Regulate Classical Activation of Microglia

“…The novel EP2 potentiator TG3-95-1 (referred to as compound 1 in Ref. 27) and EP2 antagonist TG4-155 were synthesized in our laboratory (27)(28)(29). All plasticware and reagents were endotoxin-free.…”

Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets

“…The most significantly activated regulator, however, was PTGER2, which promotes tumor cell proliferation as well as invasion and angiogenesis. 34 This finding was unexpected, and indicates that immune mechanisms are activated in tumors of higher grade. The observation may be exploited clinically, as COX2 inhibitors and selective PTGER2 inhibitors are available for targeting of PTGER2 in tumors.…”

“…The observation may be exploited clinically, as COX2 inhibitors and selective PTGER2 inhibitors are available for targeting of PTGER2 in tumors. 34 Small intestinal neuroendocrine tumors are characterized by recurrent chromosomal alterations, the most frequent involving loss of chromosome 18. Chromosomal gains involving chromosomes 4, 5, 7, 14 and 20 are observed in a small proportion of tumors and have been associated with shorter survival.…”

Analysis of how the production and activity of PGD2 affects glioma cell lines.

“…When Jiang and Dingledine activated EP2 it promoted prostate cancer cell growth and invasion as well as upregulating tumor-promoting inflammatory cytokines like IL-6 (Jiang and Dingledine, 2013). Also, when Kambe et al inhibited EP4 expression, suppression in glioma cell growth was observed (Kambe et al, 2009).…”

“…The presence of EP2 and EP4 is significant because it implies that even if PGD 2 is capable of anti-tumorigenic activity through its DP1 receptor, the abundance of PGE 2 could easily mask PGD 2 's impact by activating EP2 and EP4 signaling pathways. Looking to selectively block the PGE 2 /EP2 and PGE 2 /EP4 signaling pathways via small molecule antagonists might present a novel therapy for GBM development (Jiang and Dingledine, 2013).…”