The omega-3 polyunsaturated fatty acid eicosapentaenoic acid inhibits mouse MC-26 colorectal cancer cell liver metastasis via inhibition of PGE 2-dependent cell motility

Abstract

BACKGROUND AND PURPOSE The omega-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) has antineoplastic activity at early stages of colorectal carcinogenesis, relevant to chemoprevention of colorectal cancer (CRC). We tested the hypothesis that EPA also has anti-CRC activity at later stages of colorectal carcinogenesis, relevant to treatment of metastatic CRC, via modulation of E-type PG synthesis. EXPERIMENTAL APPROACH A BALB/c mouse model, in which intrasplenic injection of syngeneic MC-26 mouse CRC cells leads to development of liver metastases, was used. Dietary EPA was administered in the free fatty acid (FFA) form for 2 weeks before and after ultrasound-guided intrasplenic injection of 1 × 106 MC-26 cells (n= 16 each group). KEY RESULTS Treatment with 5% (w w-1) EPA-FFA was associated with a reduced MC-26 mouse CRC cell liver tumour burden compared with control animals (median liver weight 1.03 g vs. 1.62 g; P < 0.034). Administration of 5% EPA-FFA was also linked to a significant increase in tumour EPA incorporation and lower intratumoural PGE2 levels (with concomitant increased production of PGE3). Liver tumours from 5% EPA-FFA- treated mice demonstrated decreased 5-bromo-2-deoxyuridine-positive CRC cell proliferation and reduced phosphorylated ERK 1/2 expression at the invasive edge of tumours. A concentration-dependent reduction in MC-26 CRC cell Transwell® migration following EPA-FFA treatment (50-200 μM) in vitro was rescued by exogenous PGE2 (10 μM) and PGE1-alcohol (1 μM). CONCLUSIONS AND IMPLICATIONS EPA-FFA inhibits MC-26 CRC cell liver metastasis. EPA incorporation is associated with a 'PGE2 to PGE 3 switch' in liver tumours. Inhibition of PGE2-EP 4 receptor-dependent CRC cell motility probably contributes to the antineoplastic activity of EPA. © 2012 The British Pharmacological Society.