Ras signaling originates from transient nanoscale compartmentalized regions of the plasma membrane composed of specific proteins and lipids. The highly specific lipid composition of these nanodomains, termed nanoclusters, facilitates effector recruitment and therefore influences signal transduction. This suggests that Ras nanocluster proteolipid composition could represent a novel target for future chemoprevention interventions. There is evidence that consumption of fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) such as eicosapentaenoic acid (EPA, 20:5) and docosahexaenoic acid (DHA, 22:6) may reduce colon cancer risk in humans, yet the mechanism underlying this effect is unknown. Here, we demonstrate that dietary n-3 PUFA reduce the lateral segregation of cholesterol-dependent and -independent nanoclusters, suppressing phosphatidic acid-dependent oncogenic KRas effector interactions, via their physical incorporation into plasma membrane phospholipids. This results in attenuation of oncogenic Ras-driven colonic hyperproliferation in both and murine models. These findings demonstrate the unique properties of dietary n-3 PUFA in the shaping of Ras nanoscale proteolipid complexes and support the emerging role of plasma membrane-targeted therapies. The influence of dietary long chain n-3 polyunsaturated fatty acids on plasma membrane protein nanoscale organization and KRas signaling supports development of plasma membrane-targeted therapies in colon cancer. http://cancerres.aacrjournals.org/content/canres/78/14/3899/F1.large.jpg .

Background To investigate the effect of RS on acute glycemic or insulinemic responses, the FDA indicates that control and RS-enriched foods must contain equivalent amounts of digestible carbohydrate. However, RS-containing foods typically contain less digestible carbohydrate per serving than control foods. Thus, controlling for digestible carbohydrate may yield different responses as compared with controlling for serving size. Objective To compare the postprandial metabolic responses to native wheat starch (NWS) versus resistant starch type 4 (RS4) using digestible carbohydrate-matched portions compared to weight-matched portions. Methods A single-blinded randomized-controlled crossover trial examined glycemic and insulinemic responses over two hours following consumption of four cracker conditions and a dextrose beverage in apparently healthy participants (n = 14). Crackers provided 50g of digestible carbohydrate (CHO) using the FDA's meal-intervention protocol, or 35g of CHO by weight for the marketplace substitution method. Crackers differed only by the type of starch additive: NWS (MidsolTM 50) or RS4 (Fibersym® RW). Glucose levels were assessed at baseline, 15, 30, 45, 60, 90, and 120 minutes; insulin levels were measured at baseline, 30, 60, and 120 minutes. Results There were no significant differences between 50g digestible CHO cracker conditions for glucose or insulin iAUC. The 35g CHO by weight conditions were not different for glucose iAUC (Mean (95% CI); 35g NWS: 1317 (677, 2169), 35g RS4: 701 (262, 1351), p > 0.05). However, insulin iAUC was lower following 35g RS4 compared to 35g NWS (35RS4: 92 (10, 259), 35NWS: 697 (397, 1080), p < 0.01). Conclusion In healthy adults, consumption of RS4 crackers decreased postprandial insulin responses compared with NWS crackers when using the marketplace substitution method compared to the FDA standard testing method, with similar postprandial glucose responses. Comparisons of the FDA standard testing method and the marketplace substitution method should be investigated further to elucidate differential physiological impacts on consumers.

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