title: The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells.
abstract: Accumulating evidence indicates that elevated levels of prostaglandin E(2) (PGE(2)) can increase intestinal epithelial cell proliferation, and thus play a role in colorectal tumorigenesis. PGE(2) exerts its effects through four G-protein-coupled PGE receptor (EP) subtypes, named the EP1, EP2, EP3, and EP4. Increased phosphorylation of extracellular regulated kinases (ERK1/2) is required for PGE(2) to stimulate cell proliferation of human colon cancer cells. However, the EP receptor(s) that are involved in this process remain unknown. We provide evidence that L-161,982, a selective EP4 receptor antagonist, completely blocks PGE(2)-induced ERK phosphorylation and cell proliferation of HCA-7 cells. In order to identify downstream target genes of ERK1/2 signaling, we found that PGE(2) induces expression of early growth response gene-1 (EGR-1) downstream of ERK1/2 and regulates its expression at the level of transcription. PGE(2) treatment induces phosphorylation of cyclic AMP response element binding protein (CREB) at Ser133 residue and CRE-mediated luciferase activity in HCA-7 cells. Studies with dominant-negative CREB mutant (ACREB) provide clear evidence for the involvement of CREB in PGE(2) driven egr-1 transcription in HCA-7 cells. In conclusion, this study reveals that egr-1 is a target gene of PGE(2) in HCA-7 cells and is regulated via the newly identified EP4/ERK/CREB pathway. Finally our results support the notion that antagonizing EP4 receptors may provide a novel therapeutic approach to the treatment of colon cancer.
authors.affiliation: Department of Pathology, Arizona Cancer Center, University of Arizona, 1501N Campbell Avenue # 550, Tucson, AZ 85724, USA.
authors.forename: Durga Prasad
authors.initials: DP
authors.lastname: Cherukuri
authors.forename: Xiao B O
authors.initials: XB
authors.lastname: Chen
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Goulet
authors.forename: Robert N
authors.initials: RN
authors.lastname: Young
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Han
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Heimark
authors.forename: John W
authors.initials: JW
authors.lastname: Regan
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Meuillet
authors.forename: Mark A
authors.initials: MA
authors.lastname: Nelson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000502:physiology*; D013876:Thiophenes / Q000378:metabolism*; D014158:Transcription, Genetic; D014230:Triazoles / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C508711:L-161982; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013876:Thiophenes; D014230:Triazoles; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone