The omega-3 polyunsaturated fatty acid eicosapentaenoic acid inhibits mouse MC-26 colorectal cancer cell liver metastasis via inhibition of PGE2-dependent cell motility.
OBJECTIVE
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.


METHODS
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).


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
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.
Section of Molecular Gastroenterology, Leeds Institute of Molecular Medicine, St James's University Hospital, UK.
G
G
Hawcroft
M
M
Volpato
G
G
Marston
N
N
Ingram
S L
SL
Perry
A J
AJ
Cockbain
A D
AD
Race
A
A
Munarini
A
A
Belluzzi
P M
PM
Loadman
P L
PL
Coletta
M A
MA
Hull
D000527:Alprostadil / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; C033246:prostaglandin E3; D015118:Eicosapentaenoic Acid; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000527:Alprostadil; D015232:Dinoprostone