Prostaglandin E₂ regulates tumor angiogenesis in prostate cancer

In cancer management, the cyclooxygenase (COX)-targeted approach has shown great promise in anticancer therapeutics. However, the use of COX-2 inhibitors has side effects and health hazards; thus, targeting its major metabolite prostaglandin E₂ (PGE₂)-mediated signaling pathway might be a rational approach for the next generation of cancer management. Recent studies on several in vitro and in vivo models have revealed that elevated expression of COX-2 correlates with prostate tumor growth and angiogenesis. In this study, we have shown the in-depth molecular mechanism and the PGE ₂ activation of the epidermal growth factor receptor and β3 integrin through E prostanoid 2 (EP2)-mediated and EP4-mediated pathways, which lead to activator protein-1 (AP-1) activation. Moreover, PGE₂ also induces activating transcription factor-4 (ATF-4) activation and stimulates crosstalk between ATF-4 and AP-1, which is unidirectional toward AP-1, which leads to the increased expressions of urokinase-type plasminogen activator and vascular endothelial growth factor and, eventually, regulates prostate tumor cell motility. In vivo Matrigel angiogenesis assay data revealed that PGE ₂ induces angiogenesis through EP2 and EP4. Human prostate cancer specimen analysis also supported our in vitro and in vivo studies. Our data suggest that targeting PGE₂ signaling pathway (i.e., blocking EP2 and EP4 receptors) might be a rational therapeutic approach for overcoming the side effects of COX-2 inhibitors and that this might be a novel strategy for the next generation of prostate cancer management.