Role of ω-3 polyunsaturated fatty acids on cyclooxygenase-2 metabolism in brain-metastatic melanoma

Cyclooxygenase-2 (COX-2) is important in the progression of epithelial tumors. Evidence indicates that omega-6 PUFAs such as arachidonic acid ( AA) promote the growth of tumor cells; however, omega-3 fatty acids [ eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] inhibit tumor cell proliferation. We investigated the effects of omega-3 PUFA on the expression and function of COX-2 in 70W, a human melanoma cell line that metastasizes to the brain in nude mice. We show that 1) tumor necrosis factor-alpha upregulates the expression of both COX-2 mRNA and prostaglandin E-2 (PGE(2)) production, and 2) omega-3 and omega-6 PUFA regulate COX-2 mRNA expression and PGE(2) production. AA increased COX-2 mRNA expression and prostaglandin production in omega-6-stimulated 70W cells. Conversely, COX-2 mRNA expression decreased in cells incubated with EPA or DHA. AA increased Matrigel T invasion 2.4-fold, whereas EPA or DHA did not. Additionally, PGE(2) increased in vitro invasion 2.5-fold, whereas exposure to PGE(3) significantly decreased invasion. Our results demonstrate that incubation of 70W cells with either AA or PGE(2) increased invasiveness, whereas incubation with EPA or DHA downregulated both COX-2 mRNA and protein expression, with a subsequent decrease in Matrigel T invasion. Taken together, these results indicate that omega-3 PUFA regulate COX-2-mediated invasion in brain-metastatic melanoma.