Prostaglandin E 2 stimulates urokinase-type plasminogen activator receptor via EP2 receptor-dependent signaling pathways in human AGS gastric cancer cells.

Aberrant expression of urokinase-type plasminogen activator receptor (uPAR) has been observed in human gastric cancers. Prostaglandin E ₂ (PGE ₂ ), whose biosynthesis is catalyzed by cyclooxygenase-2 (COX-2), is implicated in cancer metastasis; however, the cellular and molecular mechanisms of PGE ₂ -driven uPAR expression are yet to be elucidated in human gastric cancer AGS cells. In this study, we showed that PGE ₂ induces uPAR expression in concentration- and time-dependent manners. Furthermore, using antagonists and siRNA, we found that among the four subtypes of PGE ₂ receptors, EP2 receptors are involved in PGE ₂ -induced uPAR expression. PGE ₂ induced the activation of Src, epidermal growth factor receptor (EGFR), c-Jun NH ₂ -terminal kinase (JNK), extracellular signal-regulated kinase (Erk), and p38 mitogen activated protein kinase (p38 MAPK). Specific inhibitor and mutagenesis studies showed that Src, EGFR, JNK1/2, and Erk1/2 are involved in PGE ₂ -induced uPAR expression. PGE ₂ induces EP2-dependent phosphorylation of Src, while the activation of Src-dependent EGFR leads to the phosphorylation of JNK1/2 and Erk1/2. Deletion and site-directed mutagenesis studies demonstrated the involvement of transcription factor activator protein (AP)-1 and nuclear factor-kappa B (NF-κB) in PGE ₂ -induced uPAR expression. EGFR-dependent MAPKs (JNK1/2 and Erk1/2) function as the upstream signaling molecules in the activation of AP-1 and NF-κB, respectively. AGS cells pre-treated with PGE ₂ showed remarkably enhanced invasiveness, which was partially abrogated by uPAR-neutralizing antibodies. To the best of our knowledge, this is the first report that PGE ₂ -induced uPAR expression, which stimulates invasiveness of human gastric cancer AGS cells, is mediated by the EP2 receptor-dependent Src/EGFR/JNK1/2, Erk1/2/AP-1, and Src/EGFR/JNK1/2, Erk1/2/NF-κB cascades. © 2016 Wiley Periodicals, Inc.
(© 2016 Wiley Periodicals, Inc.)