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The EP4 Receptor Antagonist, L-161,982, Blocks Prostaglandin E2-induced Signal Transduction and Cell Proliferation in HCA-7 Colon Cancer Cells

The EP4 Receptor Antagonist, L-161,982, Blocks Prostaglandin E2-induced Signal Transduction and Cell Proliferation in HCA-7 Colon Cancer Cells

Durga Prasad Cherukuri, Xiao B O Chen, Anne-Christine Goulet, Robert N Young, Yongxin Han, Ronald L Heimark, John W Regan, Emmanuelle Meuillet, Mark A Nelson

Exp Cell Res. 2007 Aug 15;313(14):2969-79.

PMID: 17631291

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP147776065	L-161,982		147776-06-5	Price

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