Prostaglandin E2 Regulates Tumor Angiogenesis in Prostate Cancer

Abstract

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 E 2 (PGE 2 )-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 B3 integrin through E prostanoid 2 (EP2)-mediated and EP4-mediated pathways, which lead to activator protein-1 (AP-1) activation. Moreover, PGE 2 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 urokinasetype 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 PGE 2 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. [Cancer Res 2008;68(19):7750-9]

Identification of EP4 as a Potential Target for the Treatment of Castration-Resistant Prostate Cancer Using a Novel Xenograft Model

“…Moreover, the xenograft tumor take-up rate of LNCaP-EP4 was higher than that of LNCaP-mock (∼100% and 60%, respectively). It was reported that PGE2 regulated angiogenesis in PC3 cells through EP2 and EP4 (44). Therefore, it was suggested that EP4 overexpression might increase cell proliferation of LNCaP cells in vivo through angiogenesis.…”

Targeting MRP4 expression by anti-androgen treatment reverses MRP4-mediated docetaxel resistance in castration-resistant prostate cancer

“…Therefore, DTX-induced AR signaling changes may be treated with anti-androgen therapy, and DTX combined with anti-androgen therapy may have a synergistic effect. Finally, prostaglandin E2 (PGE2) performs an important role in the angiogenesis, invasion and metastasis of tumor cells (33). However, PGE2 secretion by prostate cancer cells requires the involvement of MRP4 (34,35).…”

Association between CBR1 polymorphisms and NSCLC in the Chinese population

“…PGE 2 serves an important role in inhibiting apoptosisand inducing angiogenesis (20). The inactivation of PGE 2 by CBR1 may inhibit cancer angiogenesis (21), which serves an important role in the growth, progression and metastasis of cancer (22).…”