Long-Chain n-3 Fatty Acids Attenuate Oncogenic KRas-Driven Proliferation by Altering Plasma Membrane Nanoscale Proteolipid Composition

Fuentes, Natividad R, Mlih, Mohamed, Barhoumi, Rola, Fan, Yang-Yi, Hardin, Paul, Steele, Trevor J, Behmer, Spencer, Prior, Ian A ORCID: 0000-0002-4055-5161, Karpac, Jason and Chapkin, Robert S (2018) Long-Chain n-3 Fatty Acids Attenuate Oncogenic KRas-Driven Proliferation by Altering Plasma Membrane Nanoscale Proteolipid Composition. CANCER RESEARCH, 78 (14). pp. 3899-3912.

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Abstract

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, 20:5Δ5,8,11,14,17) and docosahexaenoic acid (DHA, 22:6Δ4,7,10,13,16,19) 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 Drosophila 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. Significance: 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.

Item Type:	Article
Uncontrolled Keywords:	Cells, Cultured, Cell Membrane, Animals, Mice, Drosophila, Cholesterol, Fatty Acids, Omega-3, Docosahexaenoic Acids, Eicosapentaenoic Acid, Phospholipids, Proteolipids, Fish Oils, Diet, Cell Proliferation, Proto-Oncogene Proteins p21(ras)
Depositing User:	Symplectic Admin
Date Deposited:	14 Jun 2018 11:50
Last Modified:	19 Jan 2023 01:32
DOI:	10.1158/0008-5472.CAN-18-0324
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3022571