Eicosapentaenoic acid suppresses cell proliferation in MCF-7 human breast cancer xenografts in nude rats via a pertussis toxin-sensitive signal transduction pathway.
The type and content of dietary PUFAs have profound influences on the growth rate of transplantable human breast cancers in immunodeficient rodents. Diets enriched in linoleic acid (LA), an (n-6) fatty acid, stimulate tumor growth, whereas dietary fats containing (n-3) fatty acids slow such growth. Interactions between LA and (n-3) fatty acids capable of regulating cell proliferation in solid tumors in vivo are not yet well defined. Here we tested the hypothesis that plasma eicosapentaenoic acid (EPA), an (n-3) fatty acid, suppresses cell proliferation in MCF-7 human breast cancer xenografts via a pertussis toxin-sensitive reduction of intratumor cAMP, LA uptake, and formation of the mitogen 13-hydroxyoctadecadienoic acid (13-HODE) from LA. Plasma fatty acid uptake and 13-HODE release were determined in control and EPA-treated xenografts from arteriovenous differences measured during perfusion in situ. Intratumor cAMP, extracellular signal-regulated kinase p44/p42 (ERK1/2) phosphorylation, and [3H]thymidine incorporation (TTI) were measured in tumors freeze-clamped at the end of the perfusions. Arterial blood containing EPA caused significant decreases (P < 0.05) in cAMP, uptake of SFA, monounsaturated fatty acids, and (n-6) PUFA, 13-HODE formation, ERK1/2 phosphorylation, and TTI in MCF-7 xenografts. These effects of EPA were reversed by the addition of either pertussis toxin or 8-bromoadenosine-cAMP to the EPA-containing arterial blood. Addition of 13-HODE to the EPA-containing arterial blood restored phosphorylated ERK1/2 and TTI but not FA uptake. The results suggest that EPA regulates cell proliferation in MCF-7 xenografts via a novel inhibitory G protein-coupled, (n-3) FFA receptor-mediated signal transduction pathway.
Sauer
Leonard A
LA
Bassett Research Institute, Cooperstown, NY 13326, USA. lensauermt@aol.com
Dauchy
Robert T
RT
Blask
David E
DE
Krause
Jean A
JA
Davidson
Leslie K
LK
Dauchy
Erin M
EM
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008041:Linoleic Acids / Q000494:pharmacology; D050356:Lipid Metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009368:Neoplasm Transplantation; D037342:Pertussis Toxin / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D014183:Transplantation, Heterologous
D008041:Linoleic Acids; D015124:8-Bromo Cyclic Adenosine Monophosphate; C024348:13-hydroxy-9,11-octadecadienoic acid; D015118:Eicosapentaenoic Acid; D037342:Pertussis Toxin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3