Host and direct antitumor effects and profound reduction in tumor metastasis with selective EP4 receptor antagonism.
Prostaglandin E(2) (PGE(2)), one of the major metabolites of cyclooxygenase-2, has been implicated in tumorigenesis and tumor progression in several human cancers, including colorectal and lung. Here, we show that one of the PGE(2) receptors, the EP4 receptor, plays an important role in metastasis in both of these tumor types. Using i.v. injected Lewis lung carcinoma (3LL), we found that tumor metastasis to lung was significantly reduced when mice were treated with a specific EP4 antagonist ONO-AE3-208 or when EP4 receptor expression was knocked down in the tumor cells using RNA interference technology. Host EP4 receptors also contributed to tumor metastasis and tumor growth with decreased metastasis and tumor growth observed in EP4 receptor knockout animals. In vitro tumor cell adhesion, motility, invasion, colony formation, and Akt phosphorylation were all significantly inhibited when 3LL cells were treated with the EP4 receptor-specific antagonist. When the cells were treated with an EP4-specific agonist (AE1-734), we observed a worsening of these same features in vitro. Treatment with ONO-AE3-208 also profoundly decreased liver metastases after intrasplenic injection of MC26 colon cancer cells. Our data show that selective antagonism of EP4 receptor signaling results in a profound reduction in lung and colon cancer metastasis. Selective antagonism of the EP4 receptor may thus represent a novel therapeutic approach for the treatment of cancer and especially its propensity to metastasize.
Yang
Li
L
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. li.yang@vanderbilt.edu
Huang
Yuhui
Y
Porta
Rut
R
Yanagisawa
Kiyoshi
K
Gonzalez
Adriana
A
Segi
Eric
E
Johnson
David H
DH
Narumiya
Shuh
S
Carbone
David P
DP
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000517:prevention & control / Q000556:secondary; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology; D015232:Dinoprostone / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006537:Heptanoates / Q000494:pharmacology; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000627:therapeutic use*; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000517:prevention & control*; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D010654:Phenylbutyrates / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013047:Specific Pathogen-Free Organisms; D014162:Transfection; D014410:Tumor Stem Cell Assay
C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D000970:Antineoplastic Agents; D006537:Heptanoates; D009281:Naphthalenes; D009363:Neoplasm Proteins; C487764:ONO4819; C545650:PTGER4 protein, human; D010654:Phenylbutyrates; C545651:Ptger4 protein, mouse; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone