THE N-3 POLYUNSATURATED FATTY ACID EPA DECREASES PANCREATIC CANCER CELL GROWTH IN VITRO

Abstract

Background and Aims: Epidemiologic studies suggest that fish oil, rich in n-3 polyunsaturated fatty acids (PUFAs), possesses anti-tumor activity. This effect may be mediated by an increase in cyclooxygenase (COX)-generated anti-inflammatory prostaglandin species, e.g. PGE3, and/or by activation of nuclear receptors. The aim of the present study was to evaluate the anti-tumor effects of the n-3 PUFA eicosapentaenoic acid (EPA) in pancreatic cancer cells in vitro and to evaluate the underlying mechanisms. Methods and Results: The human pancreatic cancer (PaCa) cell lines BxPC-3 (positive for COX-1 and COX-2) and MIA PaCa-2 (COX-2 negative, COX-1 positive) were cultured in serum-free medium with 10 μM EPA for 24 and 48 hours. EPA significantly reduced the number of BxPC-3 and MIA PaCa-2 cells after 24 and 48 hours as determined by cell count. Pretreatment with the highly selective COX-2 inhibitor CAY10404 (1 nM) attenuated the effect of EPA on the growth of BxPC-3 but not MIA PaCa-2 cells, which was reversed by adding exogenous PGE3 (10 μM). A selective COX-1 inhibitor SC-560 (1 nM) had no effect in either cell line. It is known that PGE signals through binding to EP receptors (EP1-4) on the cell surface. The effect of EPA on cell growth in BxPC-3 cells was inhibited by the combined EP1/2 antagonist AH6809 (10 μM) and the selective EP4 antagonist ONO-AE3-208 (10 μM), but not by selective EP1 or EP3 antagonists. Conclusions: EPA decreases the growth of PaCa cells in vitro. In COX-2 positive PaCa cells the effect of EPA is mediated by binding of COX-2 generated PGE3 to EP2 and/or EP4 receptors. The growth-inhibitory effect of EPA in COX-2 negative PaCa cells likely is mediated by COX independent mechanisms. Supported by NIH #CA104027 (G.E.) and the Hirshberg Foundation for Pancreatic Cancer Research.