THE N-3 POLYUNSATURATED FATTY ACID EPA INHIBITS PANCREATIC CANCER CELL GROWTH BY COX-2 DEPENDENT AND INDEPENDENT MECHANISMS.

Abstract

Background and Aim: Epidemiologic studies suggest that n-3 polyunsaturated fatty acids (PUFA) have negative effects on cancer development and growth. We have previously demonstrated that the n-3 PUFA EPA decreased the growth of human pancreatic cancer (PaCa) cells in vitro. The aim of the present study was to further characterize the mechanisms of the EPA-mediated decrease in PaCa cell growth in vitro. Methods and Results: The human PaCa cell lines BxPC-3 (COX-1 and COX-2 positive) and MIA PaCa-2 (COX-1 positive and COX-2 negative) were cultured in serum-free medium in the presence of EPA (0-100 micromolar) for 24 hours. EPA significantly reduced the growth of both cell lines as determined by cell count and MTT assay. The effect of EPA on BxPC-3 cell growth was partially attenuated by a selective COX-2 but not a COX-1 inhibitor. The effect of the COX-2 inhibitor on the EPA-mediated reduction of BxPC-3 cell growth was partially reversed by the addition of PGE3. Moreover, the effect of EPA on BxPC-3 cell growth was partially inhibited by antagonists against the PGE receptors EP2 and EP4. The expression of EP2 and EP4 receptors in PaCa cells was confirmed by real-time PCR. The growth-inhibitory effect of EPA in MIA PaCa-2 cells was unaffected by selective COX-1 and -2 inhibitors as well as EP2 and EP4 receptor antagonists. However, pre-incubation with GW9662, an antagonist against the nuclear receptor PPAR-gamma, completely reversed the effect of EPA on MIA PaCa-2 cell growth. Conclusions: Our studies demonstrate that the n-3 PUFA EPA decreases the growth of pancreatic cancer cell lines by COX-2 dependent and -independent mechanisms. The COX-2 independent mechanisms of EPA-induced growth inhibition were mediated by the nuclear receptor PPAR-gamma. These data provide the rationale for evaluating the efficacy of n-3 PUFAs in preclinical models of pancreatic cancer.