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

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, 20:5) 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 .

Docosahexaenoic Acid Suppresses Silica-Induced Inflammasome Activation and IL-1 Cytokine Release by Interfering With Priming Signal

“…Both TLR4 and IL-1R1 activation require the oligomerization of multiple receptors, a process that requires structural alteration of the plasma membrane (73, 74). Increased phospholipid ω-3 PUFA content reduces the formation of lipid rafts, thus suppressing inflammatory signaling pathways that depend on clustering of transmembrane receptors (73–75). Alternatively, free DHA can be cleaved from the membrane and act as a ligand for anti-inflammatory receptors.…”

Membrane therapy using DHA suppresses epidermal growth factor receptor signaling by disrupting nanocluster formation

“…There is a critical need for the development of novel anti-EGFR targeted therapies as patients utilizing current therapies often exhibit undesirable side effects ( 5 ) or develop acquired resistance ( 6 , 7 ). A large body of epidemiological, preclinical, and clinical evidence supports the role of DHA as an adjuvant therapy for colon cancer ( 12 , 13 , 14 , 15 , 16 , 17 , 18 ). However, if DHA is to be pursued as an alternative/complementary strategy for anti-EGFR therapy, the mechanism by which it suppresses EGFR signaling must be elucidated.…”

Eicosapentaenoic Acid Inhibits KRAS Mutant Pancreatic Cancer Cell Growth by Suppressing Hepassocin Expression and STAT3 Phosphorylation

“…Several studies reported that the potential capabilities of n-3 PUFAs, including DHA and EPA, not only improve the efficacy and tolerability of conventional anti-cancer treatments but also protect the host from drug-related toxicity [ 25 , 26 ]. Additionally, dietary n-3 PUFAs in genetic KRas G12D mutant mice in vivo and in vitro show that n-3 PUFAs physically merged into a phospholipids layer of the cellular membrane to reduce the lateral segmentation of cholesterol-dependent and independent nanoclusters and accordingly inhibit the interaction of oncogenic KRAS signaling effectors [ 27 ], implying that the disruption of membrane nanoclustering might overcome oncogenic KRAS -induced tumorigenesis and cancer progression. Indeed, n-3 PUFAs induce apoptosis and suppress cell proliferation in KRAS -mutant-derived pancreas nestin-expressing HPNE- KRAS G12D cells both in vitro and in vivo by reducing AKT phosphorylation [ 28 ].…”