Antagonism of the prostaglandin E receptor EP4 inhibits metastasis and enhances NK function.
Cyclooxygenase-2 (COX-2) is associated with aggressive breast cancers. The COX-2 product prostaglandin E(2) (PGE(2)) acts through four G-protein-coupled receptors designated EP1-4. Malignant and immortalized normal mammary epithelial cell lines express all four EP. The EP4 antagonist AH23848 reduced the ability of tumor cells to colonize the lungs or to spontaneously metastasize from the mammary gland. EP4 gene silencing by shRNA also reduced the ability of mammary tumor cells to metastasize. Metastasis inhibition was lost in mice lacking either functional Natural Killer (NK) cells or interferon-gamma. EP4 antagonism inhibited MHC class I expression resulting in enhanced ability of NK cells to lyse mammary tumor target cells. These studies support the hypothesis that EP4 receptor antagonists reduce metastatic potential by facilitating NK-mediated tumor cell killing and that therapeutic targeting of EP4 may be an alternative approach to the use of COX inhibitors to limit metastatic disease.
Kundu
Namita
N
Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Ma
Xinrong
X
Holt
Dawn
D
Goloubeva
Olga
O
Ostrand-Rosenberg
Suzanne
S
Fulton
Amy M
AM
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D007694:Killer Cells, Natural / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000276:immunology; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors* / Q000235:genetics; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction
C545651:Ptger4 protein, mouse; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype
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