title: Prostaglandin E2 promotes lung cancer cell migration via EP4-betaArrestin1-c-Src signalsome.
abstract: Many human cancers express elevated levels of cyclooxygenase-2 (COX-2), an enzyme responsible for the biosynthesis of prostaglandins. Available clinical data establish the protective effect of COX-2 inhibition on human cancer progression. However, despite these encouraging outcomes, the appearance of unwanted side effects remains a major hurdle for the general application of COX-2 inhibitors as effective cancer drugs. Hence, a better understanding of the molecular signals downstream of COX-2 is needed for the elucidation of drug targets that may improve cancer therapy. Here, we show that the COX-2 product prostaglandin E(2) (PGE(2)) acts on cognate receptor EP4 to promote the migration of A549 lung cancer cells. Treatment with PGE(2) enhances tyrosine kinase c-Src activation, and blockade of c-Src activity represses the PGE(2)-mediated lung cancer cell migration. PGE(2) affects target cells by activating four receptors named EP1 to EP4. Use of EP subtype-selective ligand agonists suggested that EP4 mediates prostaglandin-induced A549 lung cancer cell migration, and this conclusion was confirmed using a short hairpin RNA approach to specifically knock down EP4 expression. Proximal EP4 effectors include heterotrimeric Gs and betaArrestin proteins. Knockdown of betaArrestin1 expression with shRNA significantly impaired the PGE(2)-induced c-Src activation and cell migration. Together, these results support the idea that increased expression of the COX-2 product PGE(2) in the lung tumor microenvironment may initiate a mitogenic signaling cascade composed of EP4, betaArrestin1, and c-Src which mediates cancer cell migration. Selective targeting of EP4 with a ligand antagonist may provide an efficient approach to better manage patients with advanced lung cancer.
authors.affiliation: Department of Pathology, Medical College of Georgia, Augusta, Georgia, USA.
authors.forename: Jae Il
authors.initials: JI
authors.lastname: Kim
authors.forename: Vijayabaskar
authors.initials: V
authors.lastname: Lakshmikanthan
authors.forename: Nicole
authors.initials: N
authors.lastname: Frilot
authors.forename: Yehia
authors.initials: Y
authors.lastname: Daaka
mesh_terms: D019390:Arrestins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured; D000071557:beta-Arrestins; D019061:src-Family Kinases
chemical_list: D019390:Arrestins; C545650:PTGER4 protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000071557:beta-Arrestins; D051546:Cyclooxygenase 2; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D015232:Dinoprostone