AB063. A prostaglandin E (PGE) receptor EP4 is involved in the cell growth and invasion of prostate cancer via the cAMP-PKA/PI3K-AKT signaling pathway

BACKGROUND: Prostate cancer (PCa) is one of the most prevalent diagnosed malignancies in the world. Previous studies have proved that prostaglandin E(2) (PGE(2)) was closely related to the tumorigenesis and progression of PCa. However, the molecular mechanisms are not very clear, and it is necessary to be further studied. MMPs, RANKL and RUNX2, involved in the cell growth and bone metastasis, are activated or overexpressed in many cancers, including PCa. METHODS: This study was designed to demonstrate the internal relationship and molecular mechanisms among the PGE(2), EP4 and MMPs, RANKL and RUNX2 in PCa, and to define their roles in PCa cell proliferation and invasion. RESULTS: The results in this study showed that the protein and the mRNA expression levels of the MMP-2, MMP-9, RANKL and RUNX2 in PC3 cells were significantly upregulated by treated with PGE(2), and knockdown of these proteins blocked PGE(2)-induced cell proliferation and invasion in PC3 cells. The effect of PGE(2) on the protein and mRNA expression levels was mainly regulated via the EP4 receptor. EP4 receptor signaling activated cAMP-PKA signaling pathway, and forskolin, the activator of the adenylate cyclase (AC), has similar effects of the EP4 receptor agonist on the protein expression, while SQ22536, the inhibitor of AC, inhibited the protein expression. These results confirmed the AC/cAMP pathway was involved in EP4 receptor-mediated protein expression upregulation. By using specific inhibitor of PKA, it is demonstrated that cAMP/PKA was also related to the upregulation of the EP4 receptor-mediated protein expression. In addition to the signaling pathway of the PKA, the EP4 receptor also exerts activities through activating Akt kinase. The results in present study confirmed the hypothesis that the EP4 receptor-mediated protein expression of PCa cells, which were pretreated with the specific inhibitor of PI3K, was significantly inhibited. CONCLUSIONS: In summary, it is revealed that PGE(2) significantly upregulates the mRNA and protein expression levels of the MMPs, RANKL and RUNX2, and the EP4 receptor was involved in the cell proliferation and invasion of PCa via the cMAP-PKA/PI3K-AKT signaling pathway in this study. The present study may provide a new way of thinking and therapeutic strategy for the prevention and treatment of PCa.