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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
Author(s) -
Hawcroft G,
Volpato M,
Marston G,
Ingram N,
Perry SL,
Cockbain AJ,
Race AD,
Munarini A,
Belluzzi A,
Loadman PM,
Coletta PL,
Hull MA
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.01882.x
Subject(s) - eicosapentaenoic acid , colorectal cancer , metastasis , polyunsaturated fatty acid , omega 3 fatty acid , medicine , endocrinology , fatty acid , cell growth , chemistry , cancer research , cancer , biochemistry , docosahexaenoic acid
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 × 10 6 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 PGE 2 levels (with concomitant increased production of PGE 3 ). 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 PGE 2 (10 µM) and PGE 1 ‐alcohol (1 µM). CONCLUSIONS AND IMPLICATIONS EPA‐FFA inhibits MC‐26 CRC cell liver metastasis. EPA incorporation is associated with a ‘PGE 2 to PGE 3 switch’ in liver tumours. Inhibition of PGE 2 ‐EP 4 receptor‐dependent CRC cell motility probably contributes to the antineoplastic activity of EPA.