title: 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 beta3 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 cross-talk 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 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.
authors.affiliation: National Center for Cell Science, Pune, India.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jain
authors.forename: Goutam
authors.initials: G
authors.lastname: Chakraborty
authors.forename: Remya
authors.initials: R
authors.lastname: Raja
authors.forename: Smita
authors.initials: S
authors.lastname: Kale
authors.forename: Gopal C
authors.initials: GC
authors.lastname: Kundu
mesh_terms: D051701:Activating Transcription Factor 4 / Q000502:physiology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D015232:Dinoprostone / Q000494:pharmacology / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000209:etiology*; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D018078:Receptors, Prostaglandin E / Q000502:physiology; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014183:Transplantation, Heterologous; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D039661:Integrin beta3; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; C545645:Ptger2 protein, mouse; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D051701:Activating Transcription Factor 4; D066246:ErbB Receptors; D014568:Urokinase-Type Plasminogen Activator; D015232:Dinoprostone