Omega-6 (-6) polyunsaturated fatty acids (PUFA), abundant in the Western diet, are precursors for a number of key mediators of inflammation including the 2-series of prostaglandins (PG). PGE 2, a cyclooxygenase (COX) metabolite of arachidonic acid, a -6 PUFA, is a potent mediator of inflammation and cell proliferation. Dietary supplements rich in -3 PUFA reduce the concentrations of 2-series PG and increase the synthesis of 3-series PG (e.g., PGE 3 ), which are believed to be less inflammatory. However, studies on cellular consequences of increases in 3-series PG in comparison to 2-series PG have not been reported. In this study, we compared the effects of PGE 2 and PGE3 on (i) cell proliferation in NIH 3T3 fibroblasts, (ii) expression and transcriptional regulation of the COX-2 gene in NIH 3T3 fibroblasts, and (iii) the production of an inflammatory cytokine, IL-6, in RAW 264.7 macrophages. PGE 3, unlike PGE2, is not mitogenic to NIH 3T3 fibroblasts. PGE 2 and PGE3 both induce COX-2 mRNA via similar signaling mechanisms; however, compared with PGE 2, PGE3 is significantly less efficient in inducing COX-2 gene expression. Furthermore, although both PGE2 and PGE3 induce IL-6 synthesis in RAW 264.7 macrophages, PGE 3 is substantially less efficient compared with PGE2. We further show that increasing the -3 content of membrane phospholipid results in a decrease in mitogen-induced PGE2 synthesis. Taken together, our data suggest that successful replacement of -6 PUFA with -3 PUFA in cell membranes can result in a decreased cellular response to mitogenic and inflammatory stimuli.

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We examined whether reduced levels of Apolipoprotein A-I (apoA-I) in ovarian cancer patients are causal in ovarian cancer in a mouse model. Mice expressing a human apoA-I transgene had (i) increased survival (P < 0.0001) and (ii) decreased tumor development (P < 0.01), when compared with littermates, following injection of mouse ovarian epithelial papillary serous adenocarcinoma cells (ID-8 cells). ApoA-I mimetic peptides reduced viability and proliferation of ID8 cells and cis-platinum-resistant human ovarian cancer cells, and decreased ID-8 cell-mediated tumor burden in C57BL/6J mice when administered subcutaneously or orally. Serum levels of lysophosphatidic acid, a well-characterized modulator of tumor cell proliferation, were significantly reduced (>50% compared with control mice, P < 0.05) in mice that received apoA-I mimetic peptides (administered either subcutaneously or orally), suggesting that binding and removal of lysophosphatidic acid is a potential mechanism for the inhibition of tumor development by apoA-I mimetic peptides, which may serve as a previously unexplored class of anticancer agents.