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 ω-6 PUFAs such as arachidonic acid (AA) promote the growth of tumor cells; however, ω-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] inhibit tumor cell proliferation. We investigated the effects of ω-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-α upregulates the expression of both COX-2 mRNA and prostaglandin E₂ (PGE₂) production, and 2) ω-3 and ω-6 PUFA regulate COX-2 mRNA expression and PGE₂ production. AA increased COX-2 mRNA expression and prostaglandin production in ω-6-stimulated 70W cells. Conversely, COX-2 mRNA expression decreased in cells incubated with EPA or DHA. AA increased Matrigel™ invasion 2.4-fold, whereas EPA or DHA did not. Additionally, PGE₂ increased in vitro invasion 2.5-fold, whereas exposure to PGE₃ significantly decreased invasion. Our results demonstrate that incubation of 70W cells with either AA or PGE₂ increased invasiveness, whereas incubation with EPA or DHA downregulated both COX-2 mRNA and protein expression, with a subsequent decrease in Matrigel™ invasion. Taken together, these results indicate that ω-3 PUFA regulate COX-2-mediated invasion in brain-metastatic melanoma.