Prostaglandin E2 Promotes Lung Cancer Cell Migration via EP4-βArrestin1-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 βArrestin proteins. Knockdown of βArrestin1 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, βArrestin1, 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. Mol Cancer Res; 8(4); 569-77. ©2010 AACR.

Prostaglandin E2 Regulates Renal Cell Carcinoma Invasion through the EP4 Receptor-Rap GTPase Signal Transduction Pathway

“…Control RCC7 cells (EV) were similarly generated using pcDNA3.1 empty vector. EP4 knockdown with shRNA was peformed exactly as described in an earlier publication (24). Knockdown of endogenous Epac1 and -2 was achieved with Dharmacon ON-TARGETplus SMARTpool.…”

“…Emerging evidence implicates prostaglandins in cancer cell migration (23,24). In this study, we explored the possible involvement of EPs and their downstream effectors in kidney cancer cell invasion.…”

βArrestin1 Regulates the Guanine Nucleotide Exchange Factor RasGRF2 Expression and the Small GTPase Rac-mediated Formation of Membrane Protrusion and Cell Motility

“…␤Arrestins, including ␤arrestin1 (␤Arr1 also known as Arr2) and ␤Arr2 (also known as Arr3), were initially characterized based on their ability to regulate G protein-coupled receptor (GPCR) signaling (6), and they have been implicated in human cancers (7)(8)(9)(10). Emerging evidence shows that ␤Arr1 and ␤Arr2 also function as adaptors to transduce signals and to regulate a wide array of cellular functions, including actin remodeling and cell migration (11,12).…”

Anti-cancer Effects of MW-03, a Novel Indole Compound, by Inducing 15-Hydroxyprostaglandin Dehydrogenase and Cellular Growth Inhibition in the LS174T Human Colon Cancer Cell Line

“…Moreover, since a number of cell death mechanisms have been suggested for each indole compound, as yet unknown mechanism(s) and target(s), particularly for the second effect of MW-03, need to be investigated in more detail in not only colon cancer cells but also in other cancer cells or in normal colon cells. However, we consider those two distinct and unique effects of MW-03, or its derivatives, on colon cancer cells to be a great beneficial therapeutic tool for colon cancer treatment, or even other PGE 2 -regulated cancer such as lung cancer, 31) in the future.…”