title: Pro-migratory actions of the prostacyclin receptor in human breast cancer cells that over-express cyclooxygenase-2.
abstract: Metastasis is the major cause of death in cancer patients. Elevated expression of cyclooxygenase-2 (COX-2) is observed in many human cancers and over-production of downstream prostaglandins (PGs) has been shown to stimulate metastasis. A role for increased PGE2 production has been proposed, but whether other PGs contribute is currently unclear. In this study the pro-migratory actions of individual PGs were evaluated in MDA-MB-468 breast cancer cells that stably over-expressed COX-2 (MDA-COX-2 cells); cell migration was quantified using 3D-matrigel droplet assays. Inhibition of the prostacyclin and PGE synthases, but not alternate prostanoid synthases, prevented the increase in MDA-COX-2 cell migration produced by arachidonic acid (AA); direct treatment of cells with the stable prostacyclin analogue cicaprost also promoted migration. Pharmacological antagonism and knockdown of the IP receptor decreased cell migration, while antagonists of the alternate DP, EP2, FP, and TP prostanoid receptors were inactive. In support of these findings, activation of the IP receptor also enhanced migration in the MDA-MB-468, MDA-MB-231 and A549 cell lines, and IP receptor knock-down in MDA-COX-2 cells decreased the expression of a number of pro-migratory genes. In further studies, the prostacyclin/IP receptor and PGE2/EP4 receptor pathways were found to be functionally independent and the inhibition of phosphatidylinositol 3-kinase (PI3K) and p38 mitogen-activated protein kinase (MAPK) selectively impaired the IP-receptor-dependent migration in MDA-COX-2 cells. Taken together, the prostacyclin/IP/PI3K-p38 MAPK axis has emerged as a novel pro-migratory pathway in breast cancer cells that over-express COX-2. This information could be utilized in novel treatment strategies to minimize tumor metastasis.
authors.affiliation: Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: sarah.allison@sydney.edu.au.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Allison
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, GPO Box 2471, Adelaide, SA 5001, Australia. Electronic address: Nenad.Petrovic@unisa.edu.au.
authors.forename: Nenad
authors.initials: N
authors.lastname: Petrovic
authors.affiliation: Clinical Pharmacology, Flinders University of South Australia, Bedford Park, SA 5042, Australia. Electronic address: peter.mackenzie@flinders.edu.au.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Mackenzie
authors.affiliation: Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: michael.murray@sydney.edu.au.
authors.forename: Michael
authors.initials: M
authors.lastname: Murray
mesh_terms: D016718:Arachidonic Acid / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D055786:Gene Knockout Techniques; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D011464:Epoprostenol; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D048051:p38 Mitogen-Activated Protein Kinases; C113936:PTGIR protein, human; C043867:cicaprost
keywords: Breast cancer metastasis; Cell migration; Cyclooxygenase-2; IP receptor; Prostacyclin