The beneficial effects of
omega-3 fatty acids are believed to be due in part to selective alteration of arachidonate metabolism that involves
cyclooxygenase (COX)
enzymes. Here we investigated the effect of
eicosapentaenoic acid (EPA) on the proliferation of human
non-small cell lung cancer A549 (COX-2 over-expressing) and H1299 (COX-2 null) cells as well as their xenograft models. While EPA inhibited 50% of proliferation of A549 cells at 6.05 µM, almost 80 µM of EPA was needed to reach similar levels of inhibition of H1299 cells. The formation of
prostaglandin (PG)E3 in A549 cells was almost threefold higher than that of H1299 cells when these cells were treated with EPA (25 µM). Intriguingly, when COX-2 expression was reduced by
siRNA or
shRNA in A549 cells, the antiproliferative activity of EPA was reduced substantially compared to that of control
siRNA or
shRNA transfected A549 cells. In line with this, dietary
menhaden oil significantly inhibited the growth of A549
tumors by reducing
tumor weight by 58.8 ± 7.4%. In contrast, a similar diet did not suppress the development of H1299 xenograft. Interestingly, the ratio of
PGE3 to
PGE2 in A549 was about 0.16 versus only 0.06 in H1299 xenograft tissues. Furthermore,
PGE2 up-regulated expression of pAkt, whereas
PGE3 downregulated expression of pAkt in A549 cells. Taken together, the results of our study suggest that the ability of EPA to generate
PGE3 through the COX-2
enzyme might be critical for EPA-mediated
tumor growth inhibition which is at least partly due to down-regulation of Akt phosphorylation by
PGE3.