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

Yvonne M. Denkins, Doty Kempf, Melissa Ferniz, Shilpa Nileshwar, and Dario Marchetti

Department of Comparative Biomedical Sciences, School of Veterinary Medicine Louisiana State University, Baton Rouge, LA 70803

Corresponding Author: ydenkins{at}vetmed.lsu.edu

Constitutive expression of cyclooxygenase-2 (COX-2), an inducible enzyme involved in the control of inflammatory reactions and in the catalytic conversion of polyunsaturated fatty acids (PUFA) into prostaglandins, plays a role in the development and progression of epithelial tumors. Though a large body of evidence indicates that omega $omega$ -6 PUFA such as arachidonic acid (AA) promote the growth of tumor cells, $omega$ -3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] have been shown to inhibit tumor cell proliferation. We have 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 1) that constitutive expression of COX-2 mRNA is up-regulated by TNF- $alpha$ which correlated with increased prostaglandin E₂ (PGE₂) production, and 2) regulation of both COX-2 mRNA expression and PGE₂ production upon incubation with $omega$ -3 and $omega$ -6 PUFA. COX-2 mRNA expression was significantly increased above control levels in cells incubated with AA resulting in increased prostaglandin production in $omega$ -6 stimulated 70W cells. Conversely, COX-2 mRNA expression decreased in cells incubated with either EPA or DHA. Incubation of 70W with AA increased Matrigel^TM invasion 2.4-fold whereas incubation with either EPA or DHA resulted in no change in invasive values. Additionally, incubation of 70W cells with PGE₂ resulted in a 2.5-fold increase in invasion, whereas exposure to PGE₃ significantly decreased invasion. Our results demonstrate that incubation of 70W with either AA or PGE₂ significantly increased invasiveness whereas incubation with EPA or DHA down-regulated both COX-2 mRNA and protein expression with a subsequent decrease in Matrigel^TM invasion. Taken together, these results indicate that $omega$ -3 PUFA regulate COX-2-mediated invasion in brain-metastatic melanoma.

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