title: Role of intracellular prostaglandin E₂ in cancer-related phenotypes in PC3 cells.
abstract: Prostaglandin E2 (PGE2) and hypoxia-inducible factor-1α (HIF-1α) affect many mechanisms that have been shown to play a role in prostate cancer. In PGE2-treated LNCaP cells, up-regulation of HIF-1α requires the internalization of PGE2, which is in sharp contrast with the generally accepted view that PGE2 acts through EP receptors located at the cell membrane. Here we aimed to study in androgen-independent PC3 cells the role of intracellular PGE2 in several events linked to prostate cancer progression. To this end, we used bromocresol green, an inhibitor of prostaglandin uptake that blocked the immediate rise in intracellular immunoreactive PGE2 following treatment with 16,16-dimethyl-PGE2. Bromocresol green prevented the stimulatory effect of 16,16-dimethyl-PGE on cell proliferation, adhesion, migration and invasion and on HIF-1α expression and activity, the latter assessed as the HIF-dependent activation of (i) a hypoxia response element-luciferase plasmid construct, (ii) production of angiogenic factor vascular endothelial growth factor-A and (iii) in vitro angiogenesis. The basal phenotype of PC3 cells was also affected by bromocresol green, that substantially lowered expression of HIF-1α, production of vascular endothelial growth factor-A and cell proliferation. These results, and the fact that we found functional intracellular EP receptors in PC3 cells, suggest that PGE2-dependent intracrine mechanisms play a role in prostate cancer Therefore, inhibition of the prostaglandin uptake transporter might be a novel therapeutic approach for the treatment of prostate cancer.
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Madrigal-Martínez
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
authors.forename: Francisco J Lucio
authors.initials: FJ
authors.lastname: Cazaña
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain. Electronic address: anab.fernandez@uah.es.
authors.forename: y Ana B
authors.initials: yA
authors.lastname: Fernández-Martínez
mesh_terms: D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D001961:Bromcresol Green / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism*; D008297:Male; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018078:Receptors, Prostaglandin E / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018078:Receptors, Prostaglandin E; D001961:Bromcresol Green; D003094:Collagen; D015232:Dinoprostone; D015064:16,16-Dimethylprostaglandin E2
keywords: EP receptor; Intracellular prostaglandin E2; PC3 cells; Prostate cancer; Tumor phenotypes