Prostaglandin E2 receptor EP4 is involved in the cell growth and invasion of prostate cancer via the cAMP-PKA/PI3K-Akt signaling pathway

Prostate cancer (PCa) is one of the most prevalent diagnosed malignancies globally. Previous studies have demonstrated that prostaglandin E-2 (PGE(2)) is closely associated with the tumorigenesis and progression of PCa. However, the underlying molecular mechanisms remain unclear and require further investigation. Matrix metalloproteinases (MMPs), receptor activator of nuclear factor-B ligand (RANKL) and runt-related transcription factor 2 (RUNX2), which are involved in cell growth and bone metastasis, are frequently activated or overexpressed in various types of cancer, including PCa. The present study was designed to investigate the associations between PGE(2) and the PGE(2) receptor EP4, and MMPs, RANKL and RUNX2 in PCa, and to define their roles in PCa cell proliferation and invasion in addition to understanding the molecular mechanisms. The results of western blotting and reverse transcription-quantitative polymerase chain reaction demonstrated that the protein and the mRNA expression levels of MMP-2, MMP-9, RANKL and RUNX2 in PC-3 cells were significantly upregulated by treatment with PGE(2), respectively, and knockdown of these proteins blocked PGE(2)-induced cell proliferation and invasion in PC-3 cells, as determined by Cell Counting Kit-8 and Matrigel invasion assays, respectively. The effect of PGE(2) on the protein and mRNA expression levels was primarily regulated via the EP4 receptor. EP4 receptor signaling activates the cyclic (c)AMP-protein kinase A (PKA) signaling pathway, and forskolin, an activator of adenylate cyclase (AC), exhibited similar effects to an EP4 receptor agonist on the protein expression, while SQ22536, an inhibitor of AC, inhibited the protein expression. These results confirmed that the AC/cAMP pathway may be involved in EP4 receptor-mediated upregulation of protein expression. By using a specific inhibitor of PKA, it was also demonstrated that cAMP/PKA was also involved in the EP4 receptor-mediated upregulation of protein expression. In addition to the signaling pathway involving PKA, the EP4 receptor also exerts activities through activation of Akt kinase. The results in the present study confirmed the hypothesis that EP4 receptor-mediated protein expression in PCa cells that were pretreated with a specific inhibitor of phosphatidylinositol 3-kinase (PI3K) was significantly inhibited. In conclusion, the results of the present study indicate that PGE(2) significantly upregulated the mRNA and protein expression levels of the MMP-2, MMP-9, RANKL and RUNX2, and the EP4 receptor was involved in the cell proliferation and invasion of PCa via the cAMP-PKA/PI3K-Akt signaling pathway. These results may provide novel insight into potential therapeutic strategies for the prevention and treatment of PCa.