Abstract 600: EPA derived PGE3 inhibits proliferation and angiogenesis of non-small cell lung cancer A549 cells through the EGFR and MAPKinase pathways
Authors: Pan Yong , Efuet Ekem , Cartwright Carrie , Fischer Susan M. , Yang Peiying 
Published: August 2012

Abstract
Essential fatty acids (EFA, n-3) have been implicated in lowering the incidence of atherosclerosis, inflammation and tumor cell proliferation. The beneficial effects of EFA are believed to be due, in part, to selective alteration of arachidonic acid metabolism that involves cyclooxygenase enzymes (i.e. decrease formation of PGE2 and increase formation of PGE3). We previously reported that the anti-proliferative effect of EPA in human lung cancer A549 cells is associated with formation of PGE3, a COX-2 metabolite of the fish oil EPA (J. Lipid Res. 45: 1030-1039, 2004), and the antiproliferative effect of fish oil derived EPA was differently regulated in mice bearing human lung cancer A549 (COX-2 over-expressed) or H1299 (without COX-2) xenograft tumors. Here we report the anti-proliferative effect and antiangiogenic activity of EPA derived PGE3 in NSCLC A549 and H596 cells and its associated mechanisms. PGE2, at physiologically achievable concentration (0.1 to 0.5 μM), slightly enhanced the proliferation of A549 and H596 cells (COX-2 overexpressing cells) while PGE3 moderately inhibited their proliferation by approximately 30%. In soft agar anchorage dependent assay, PGE2 appears to increase proliferation whereas PGE3 again decreased proliferation, in both A549 and H596 cells. Interestingly, there was no inhibition by PGE3 in normal human bronchial epithelial cells. While the effect of both PGE2 and PGE3 on the cell cycle in A549 and H596 showed no significant changes, determination of cell migration, using a scratch assay, resulted in a slower migration of HUVEC cells induced by PGE3 compared to PGE2. Additionally, PGE3 exhibited a dose dependent inhibition of tubular formation. Mechanistically, the MAPKinase inhibitor, PG98046 did not block the effect of PGE2, but did reduce the inhibitory effect of PGE3 in A549 cells. Treatment with PI3K inhibitor (LY294002) blocked the stimulative effect of PGE2 on the proliferation of A549 cells, but not on the effect of PGE3, suggesting that PGE2 and PGE3 might act on different receptors. This differential receptor modulation of PGE2 and PGE3 was further supported by the fact that PGE2 (0.1 to 1 μM) did not alter the levels of pCREB, whereas at similar concentrations, PGE3 inhibited the phosphorylation of CREB in A549 cells. The effect of PGE2 and PGE3 on EGFR protein was also differentially regulated evidenced by PGE3 being inhibitory for this particular protein while no changes were observed in PGE2 treated A549 cells. Taken together, the data suggest that the effect of PGE2 might be mediated through the PI3kinase pathway, while that of PGE3 might be mediated through both EGFR and MAPKinase pathways. Whether this differential regulatory effect elicited by PGE2 and PGE3 in A549 cells is mediated through the PGE2 receptor is currently under investigation. This study is supported in part by NCI Grant 1R01CA144053-01.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 600. doi:1538-7445.AM2012-600