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, di fferentiation, and apoptosis, with membrane localization of the protein bei ng a prerequisite for malignant transformation. We have recently demonstrat ed that feeding fish oil, compared with corn oil, decreases colonic Ras mem brane localization and reduces tumor formation in rats injected with a colo n carcinogen. Because the biological activity of Ras is regulated by posttr anslational lipid attachment and its interaction with stimulatory lipids, w e investigated whether docosahexaenoic acid (DHA), found in fish oil, compa red with linoleic acid (LA), found in corn oil, alters Ras posttranslationa l processing, activation, and effector protein function in young adult mous e colon cells overexpressing H-ras (YAMC-ras). We show here that the major n-3 polyunsaturated fatty acid (PUFA) constituent of fish oil, DHA, compare d with LA (an n-6 PUFA), reduces Ras localization to the plasma membrane wi thout affecting posttranslational lipidation and lowers GTP binding and dow nstream p42/44 ERK-dependent signaling. In view of the central role of onco genic 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.