Effect of eicosapentaenoic acid on E-type prostaglandin synthesis and EP4 receptor signaling in human colorectal cancer cells.
The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA), in the free fatty acid (FFA) form, has been demonstrated to reduce adenoma number and size in patients with familial adenomatous polyposis. However, the mechanistic basis of the antineoplastic activity of EPA in the colorectum remains unclear. We tested the hypothesis that EPA-FFA negatively modulates synthesis of and signaling by prostaglandin (PG) E(2) in human colorectal cancer (CRC) cells. EPA-FFA induced apoptosis of cyclooxygenase (COX)-2-positive human HCA-7 CRC cells in vitro. EPA-FFA in cell culture medium was incorporated rapidly into phospholipid membranes of HCA-7 human CRC cells and acted as a substrate for COX-2, leading to reduced synthesis of PGE(2) and generation of PGE(3). Alone, PGE(3) bound and activated the PGE(2) EP4 receptor but with reduced affinity and efficacy compared with its "natural" ligand PGE(2). However, in the presence of PGE(2), PGE(3) acted as an antagonist of EP4 receptor-dependent 3',5' cyclic adenosine monophosphate induction in naturally EP4 receptor-positive LoVo human CRC cells and of resistance to apoptosis in HT-29-EP4 human CRC cells overexpressing the EP4 receptor. We conclude that EPA-FFA drives a COX-2-dependent "PGE(2)-to-PGE(3) switch" in human CRC cells and that PGE(3) acts as a partial agonist at the PGE(2) EP4 receptor.
Hawcroft
Gillian
G
Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, United Kingdom. medgha@leeds.ac.uk
Loadman
Paul M
PM
Belluzzi
Andrea
A
Hull
Mark A
MA
D000236:Adenoma / Q000378:metabolism / Q000473:pathology*; D000527:Alprostadil / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D003470:Culture Media / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D011458:Prostaglandins E / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011485:Protein Binding / Q000187:drug effects; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003470:Culture Media; D005230:Fatty Acids, Nonesterified; D011458:Prostaglandins E; D058309:Receptors, Prostaglandin E, EP4 Subtype; C033246:prostaglandin E3; D015118:Eicosapentaenoic Acid; D000527:Alprostadil