n-6 and n-3 polyunsaturated fatty acids differentially modulate oncogenic Ras activation in colonocytes.
Ras proteins are critical regulators of cell function, including growth, differentiation, and apoptosis, with membrane localization of the protein being a prerequisite for malignant transformation. We have recently demonstrated that feeding fish oil, compared with corn oil, decreases colonic Ras membrane localization and reduces tumor formation in rats injected with a colon carcinogen. Because the biological activity of Ras is regulated by posttranslational lipid attachment and its interaction with stimulatory lipids, we investigated whether docosahexaenoic acid (DHA), found in fish oil, compared with linoleic acid (LA), found in corn oil, alters Ras posttranslational processing, activation, and effector protein function in young adult mouse colon cells overexpressing H-ras (YAMC-ras). We show here that the major n-3 polyunsaturated fatty acid (PUFA) constituent of fish oil, DHA, compared with LA (an n-6 PUFA), reduces Ras localization to the plasma membrane without affecting posttranslational lipidation and lowers GTP binding and downstream p42/44(ERK)-dependent signaling. In view of the central role of oncogenic Ras in the development of colon cancer, the finding that n-3 and n-6 PUFA differentially modulate Ras activation may partly explain why dietary fish oil protects against colon cancer development.
Collett
E D
ED
Molecular and Cell Biology Group, Faculty of Nutrition, and Center for Environmental and Rural Health, Texas A&M University, College Station, Texas 77843-2471, USA.
Davidson
L A
LA
Fan
Y Y
YY
Lupton
J R
JR
Chapkin
R S
RS
D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003106:Colon; D003314:Corn Oil; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004789:Enzyme Activation; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D043371:Fatty Acids, Omega-6; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005395:Fish Oils; D011905:Genes, ras / Q000187:drug effects*; D019787:Linoleic Acid / Q000494:pharmacology*; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D019308:Palmitic Acid / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D005231:Fatty Acids, Unsaturated; D005395:Fish Oils; D008563:Membrane Lipids; D010743:Phospholipids; D004281:Docosahexaenoic Acids; D019308:Palmitic Acid; D003314:Corn Oil; D019787:Linoleic Acid; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D015689:Oncogene Protein p21(ras)