Prostaglandin receptor EP2 is a novel molecular target for high-risk neuroblastoma

Abstract

As the third-most common type of cancers in infants and young children, neuroblastoma accounts for nearly 10% of all childhood cancers. Despite remarkable advances in tumor diagnosis and management during the past decades, the five-year survival rates for patients with high-risk neuroblastoma remain below 50%. Developing new therapies for this devastating type of childhood cancer is an urgent unmet need. Cyclooxygenase (COX) via synthesizing prostaglandin E2 (PGE2) promotes tumor cell proliferation, survival, migration and invasion, and fosters an inflammation-enriched microenvironment that can facilitate angiogenesis, immune evasion and treatment resistance. However, which downstream PGE2 receptor subtype - namely EP1, EP2, EP3 and EP4 - is directly involved in COX activity-promoted neuroblastoma growth remains elusive. Analyzing five major neuroblastoma patient datasets: Versteeg-88, Kocak-649, SEQC-498, Primary NRC-283, and Oberthuer-251, we show that COX-1/PGE2/EP2 signaling axis is highly associated with the aggressiveness of human neuroblastoma. A time-resolved fluorescence resonance energy transfer (TR-FRET) method reveals EP2 as the key Gs-coupled receptor that mediates PGE2-initiated cAMP signaling in neuroblastoma cells with various risk factors. Taking advantage of novel, selective and bioavailable small-molecule antagonists that we recently developed to target the PGE2/EP2 signaling in vivo, we have demonstrated that pharmacological inhibition of the peripheral EP2 receptor substantially impairs the growth of human neuroblastoma xenografts and the associated angiogenesis in mice. Collectively, our results suggest that the PGE2/EP2 pathway contributes to the growth and malignant potential of human neuroblastoma cells; pharmacological inhibition on EP2 receptor by our drug-like compounds might provide a novel therapeutic strategy for this deadly pediatric cancer.