Long-Chain n-3 Fatty Acids Attenuate Oncogenic KRas-Driven Proliferation by Altering Plasma Membrane Nanoscale Proteolipid Composition.
Long-Chain n-3 Fatty Acids Attenuate Oncogenic KRas-Driven Proliferation by Altering Plasma Membrane Nanoscale Proteolipid Composition.
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DOI：
10.1158/0008-5472.can-18-0324
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发表时间：
2018-07-15
期刊：
影响因子：
11.2
通讯作者：
Chapkin RS
中科院分区：
文献类型：
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作者：
Fuentes NR;Mlih M;Barhoumi R;Fan YY;Hardin P;Steele TJ;Behmer S;Prior IA;Karpac J;Chapkin RS
Ras 信号传导源自由特定蛋白质和脂质组成的质膜的瞬时纳米级分隔区域。这些纳米结构域的高度特异性脂质组成（称为纳米簇）促进效应器招募，从而影响信号转导。这表明 Ras 纳米簇蛋白脂质组合物可以代表未来化学预防干预的新靶点。有证据表明，食用含有长链 n-3 多不饱和脂肪酸 (n-3 PUFA)，如二十碳五烯酸 (EPA, 20:5Δ5,8,11,14,17) 和二十二碳六烯酸 (DHA, 22:6Δ4,7,10,13,16,19) 的鱼油可能会降低人类患结肠癌的风险，但这种作用背后的机制 未知。在这里，我们证明膳食 n-3 PUFA 通过物理掺入质膜磷脂，减少胆固醇依赖性和非依赖性纳米团簇的横向分离，抑制磷脂酸依赖性致癌 KRas 效应子相互作用。这导致果蝇和小鼠模型中致癌 Ras 驱动的结肠过度增殖减弱。这些发现证明了膳食 n-3 PUFA 在 Ras 纳米级蛋白脂质复合物塑造中的独特特性，并支持质膜靶向疗法的新兴作用。
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.