caa a22 4500 606176314 CHVBK 20210128100747.0 cr unu---uuuuu 210128e20150901xx s 000 0 eng 10.1007/s00018-015-1891-5 doi (NATIONALLICENCE)springer-10.1007/s00018-015-1891-5 Intracellular EP2 prostanoid receptor promotes cancer-related phenotypes in PC3 cells [Elektronische Daten] [Ana Fernández-Martínez, Javier Lucio-Cazaña] Prostaglandin E2 (PGE2) and hypoxia-inducible factor-1α (HIF-1α) affect many mechanisms that have been involved in the pathogenesis of prostate cancer (PC). HIF-1α, which is up-regulated by PGE2 in LNCaP cells and PC3 cells, has been shown to contribute to metastasis and chemo-resistance of castrate-resistant PC (a lethal form of PC) and to promote in PC cells migration, invasion, angiogenesis and chemoresistance. The selective blockade of PGE2-EP2 signaling pathway in PC3 cells results in inhibition of cancer cell proliferation and invasion. PGE2 affects many mechanisms that have been shown to play a role in carcinogenesis such as proliferation, apoptosis, migration, invasion and angiogenesis. Recently, we have found in PC3 cells that most of these PGE2-induced cancer-related features are due to intracellular PGE2 (iPGE2). Here, we aimed to study in PC3 cells the role of iPGE2-intracellular EP2 (iEP2)-HIF-1α signaling in several events linked to PC progression using an experimental approach involving pharmacological inhibition of the prostaglandin uptake transporter and EGFR and pharmacological and genetic modulation of EP2 receptor and HIF-1α. We found that iPGE2 increases HIF-1α expression through iEP2-dependent EGFR transactivation and that inhibition of any of the axis iEP2-EGFR-HIF-1α in cells treated with PGE2 or EP2 agonist results in prevention of the increase in PC3 cell proliferation, adhesion, migration, invasion and angiogenesis in vitro. Of note, PGE2 induced EP2 antagonist-sensitive DNA synthesis in nuclei isolated from PC3 cells, which indicates that they have functional EP2 receptors. These results suggest that PGE2-EP2 dependent intracrine mechanisms involving EGFR and HIF-1α play a role in PC. Springer Basel, 2015 Intracellular prostaglandin E2 nationallicence Prostate cancer nationallicence EP2 receptor nationallicence PC3 cells nationallicence HIF-1α nationallicence EGFR nationallicence BG : Bromocresol green nationallicence EGFR : Epidermal growth factor receptor nationallicence HIF-1α : Hypoxia-inducible factor-1α nationallicence PGE2 : Prostaglandin E2 nationallicence PGT : Prostaglandin transporter nationallicence VEGF-A : Vascular endothelial growth factor-A nationallicence HRE : HIF-responsive element nationallicence PC : Prostate cancer nationallicence Fernández-Martínez Ana Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, 28871, Madrid, Spain aut Lucio-Cazaña Javier Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, 28871, Madrid, Spain aut Cellular and Molecular Life Sciences Springer Basel 72/17(2015-09-01), 3355-3373 1420-682X 72:17<3355 2015 72 18 https://doi.org/10.1007/s00018-015-1891-5 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-015-1891-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Fernández-Martínez Ana Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, 28871, Madrid, Spain aut NATIONALLICENCE 700 1- Lucio-Cazaña Javier Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, 28871, Madrid, Spain aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/17(2015-09-01), 3355-3373 1420-682X 72:17<3355 2015 72 18