A Novel Small Molecular Prostaglandin Receptor EP4 Antagonist, L001, Suppresses Pancreatic Cancer Metastasis.

Abstract

Metastatic pancreatic cancer remains a major clinical challenge, emphasizing the urgent need for the exploitation of novel therapeutic approaches with superior response. In this study, we demonstrate that the aberrant activation of prostaglandin E2 (PGE2) receptor 4 (EP4) is a pro-metastatic signal in pancreatic cancer. To explore the therapeutic role of EP4 signaling, we developed a potent and selective EP4 antagonist L001 with single-nanomolar activity using a panel of cell functional assays. EP4 antagonism by L001 effectively repressed PGE2-elicited cell migration and the invasion of pancreatic cancer cells in a dose-dependent manner. Importantly, L001 alone or combined with the chemotherapy drug gemcitabine exhibited remarkably anti-metastasis activity in a pancreatic cancer hepatic metastasis model with excellent tolerability and safety. Mechanistically, EP4 blockade by L001 abrogated Yes-associated protein 1 (YAP)-driven pro-metastatic factor expression in pancreatic cancer cells. The suppression of YAP's activity was also observed upon L001 treatment in vivo. Together, these findings support the notions that EP4-YAP signaling axis is a vital pro-metastatic pathway in pancreatic cancer and that EP4 inhibition with L001 may deliver a therapeutic benefit for patients with metastatic pancreatic cancer.

• Authors: Jiacheng He, Xianhua Lin, Fanhui Meng, Yumiao Zhao, Wei Wang, Yao Zhang, Xiaolei Chai, Ying Zhang, Weiwei Yu, Junjie Yang, Guichao Li, Xuekui Du, Hankun Zhang, Mingyao Liu, Weiqiang Lu
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 27 Issue 4 (Feb 11 2022) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 35208999 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Receptors, Prostaglandin E, EP4 Subtype
• Dinoprostone

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Dinoprostone (metabolism, pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Hippo Signaling Pathway (drug effects)
• Humans
• Mice
• Models, Biological
• Molecular Structure
• Neoplasm Metastasis
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Receptors, Prostaglandin E, EP4 Subtype (antagonists & inhibitors, chemistry)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays