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 (PGE 2 ) 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 PGE 2 receptor subtypenamely EP1, EP2, EP3 and EP4is 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/PGE 2 /EP2 signaling axis is highly associated with the aggressiveness of human neuroblastoma. A timeresolved fluorescence resonance energy transfer (TR-FRET) method reveals EP2 as the key Gα s -coupled receptor that mediates PGE 2 -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 PGE 2 /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 PGE 2 /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.

EP2 Antagonists (2011–2021): A Decade’s Journey from Discovery to Therapeutics

“…Likewise, the inhibition of PGE 2 direct synthase mPGES-1 by Compound III (CIII) or 934 was found to suppress neuroblastoma with the MYCN amplification or 11q deletion, , attesting to an essential role for PGE 2 in the high-risk neuroblastoma. Interestingly, correlation analyses on neuroblastoma patient data sets revealed a positive relationship between the COX/PGE 2 /EP2 signaling axis and the aggressiveness of a human neuroblastoma . A cell-based TR-FRET assay method identified EP2 as the primary Gα s -coupled receptor that mediates PGE 2 -initiated cAMP signaling in neuroblastoma cells with various risk factors .…”

“…Generally, it is thought of as an overactivation of the immune system characterized by an extreme elevation of systemic cytokine circulation and hyperactive immune cells, both of which can have detrimental effects on multiorgan systems . COX-2/PGE 2 /EP2 signaling has been shown to play a considerable role in regulating the immune response, specifically through an induction of a wide array of pro-inflammatory cytokines and chemokines including IL-1β, IL-6, TNF-α, and CCL2 (MCP-1) in various disease conditions. ,,,,,, Interestingly, spike proteins of the COVID-19 virus have been shown to induce a COX-2 expression, which could implicate its involvement in facilitating the cytokine storm in COVID-19. , NSAIDs are primary medicines that are widely used to alleviate pain, fever, and inflammation, which are the common symptoms of COVID-19 patients . Indeed, treatment with NSAIDs has been demonstrated to stifle the inflammatory response to COVID-19, but it also altered the host’s ability to produce protective antibodies .…”

“…Interestingly, correlation analyses on neuroblastoma patient data sets revealed a positive relationship between the COX/PGE 2 /EP2 signaling axis and the aggressiveness of a human neuroblastoma. 197 A cell-based TR-FRET assay method identified EP2 as the primary Gα scoupled receptor that mediates PGE 2 -initiated cAMP signaling in neuroblastoma cells with various risk factors. 197 A preliminary study using compounds 4 and 7 demonstrated that pharmacological inhibition of the EP2 receptor in mice substantially impaired the growth of human neuroblastoma xenografts and the associated angiogenesis and downregulated pro-inflammatory cytokines in tumor tissues (Table 1).…”

“…197 A cell-based TR-FRET assay method identified EP2 as the primary Gα scoupled receptor that mediates PGE 2 -initiated cAMP signaling in neuroblastoma cells with various risk factors. 197 A preliminary study using compounds 4 and 7 demonstrated that pharmacological inhibition of the EP2 receptor in mice substantially impaired the growth of human neuroblastoma xenografts and the associated angiogenesis and downregulated pro-inflammatory cytokines in tumor tissues (Table 1). 197 Collectively, these preliminary results suggest that PGE 2 via EP2 receptor increases the growth and malignant potential of human neuroblastoma cells; selective EP2 antagonists might provide novel alternative therapeutic strategies to COX or mPGES-1 inhibition for this devastating type of pediatric cancer.…”

“…216 COX-2/PGE 2 /EP2 signaling has been shown to play a considerable role in regulating the immune response, specifically through an induction of a wide array of pro-inflammatory cytokines and chemokines including IL-1β, IL-6, TNF-α, and CCL2 (MCP-1) in various disease conditions. 18,21,26,38,55,157,197 Interestingly, spike proteins of the COVID-19 virus have been shown to induce a COX-2 expression, which could implicate its involvement in facilitating the cytokine storm in COVID-19. 217,218 NSAIDs are primary medicines that are widely used to alleviate pain, fever, and inflammation, which are the common symptoms of COVID-19 patients.…”