Membrane therapy using DHA suppresses epidermal growth factor receptor signaling by disrupting nanocluster formation.
Membrane therapy using DHA suppresses epidermal growth factor receptor signaling by disrupting nanocluster formation.
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DOI：
10.1016/j.jlr.2021.100026
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发表时间：
2021
影响因子：
6.5
通讯作者：
Chapkin RS
中科院分区：
文献类型：
--
作者：
Fuentes NR;Mlih M;Wang X;Webster G;Cortes-Acosta S;Salinas ML;Corbin IR;Karpac J;Chapkin RS
表皮生长因子受体（EGFR）信号驱动多种癌症的形成，包括结肠癌。二十二碳六烯酸（DHA, 22∶6Δ4,7,10,13,16,19）是一种化学保护性长链n-3多不饱和脂肪酸，可抑制EGFR信号传导。然而，这种表型背后的机制尚不清楚。因此，我们使用超分辨率显微镜技术来研究EGFR功能与dha诱导的质膜纳米结构域改变之间的机制联系。在体外（YAMC和IMCE小鼠结肠细胞系）和体内（果蝇、野生型和Fat-1小鼠）等基因模型中，通过治疗性纳米颗粒递送、内源性合成或膳食补充来增强细胞DHA可减少egfr介导的细胞增殖和下游Ras/ERK信号。DHA的磷脂掺入降低了膜刚性和EGFR纳米簇的大小。同样，质膜磷脂酸（PA）、磷脂酰肌醇-4,5-二磷酸（PIP2）或胆固醇的药理学减少与EGFR纳米簇大小的减少有关。此外，与PA或PIP2不同，在dha处理的细胞中，仅添加胆固醇就能恢复EGFR纳米级聚集。这些发现表明，DHA部分通过重塑EGFR蛋白脂纳米结构域来减少EGFR信号传导，支持使用膜疗法的可行性，即饮食/药物相关策略来靶向质膜组织，以减少EGFR信号传导和癌症风险。在多种体外和体内模型中，细胞膜磷脂富集DHA通过减少EGFR纳米簇的形成来抑制EGFR介导的表型。
Epidermal growth factor receptor (EGFR) signaling drives the formation of many types of cancer, including colon cancer. Docosahexaenoic acid (DHA, 22∶6Δ4,7,10,13,16,19), a chemoprotective long-chain n-3 polyunsaturated fatty acid suppresses EGFR signaling. However, the mechanism underlying this phenotype remains unclear. Therefore, we used super-resolution microscopy techniques to investigate the mechanistic link between EGFR function and DHA-induced alterations to plasma membrane nanodomains. Using isogenic in vitro (YAMC and IMCE mouse colonic cell lines) and in vivo (Drosophila, wild type and Fat-1 mice) models, cellular DHA enrichment via therapeutic nanoparticle delivery, endogenous synthesis, or dietary supplementation reduced EGFR-mediated cell proliferation and downstream Ras/ERK signaling. Phospholipid incorporation of DHA reduced membrane rigidity and the size of EGFR nanoclusters. Similarly, pharmacological reduction of plasma membrane phosphatidic acid (PA), phosphatidylinositol-4,5-bisphosphate (PIP2) or cholesterol was associated with a decrease in EGFR nanocluster size. Furthermore, in DHA-treated cells only the addition of cholesterol, unlike PA or PIP2, restored EGFR nanoscale clustering. These findings reveal that DHA reduces EGFR signaling in part by reshaping EGFR proteolipid nanodomains, supporting the feasibility of using membrane therapy, i.e., dietary/drug-related strategies to target plasma membrane organization, to reduce EGFR signaling and cancer risk. Cellular membrane phospholipid enrichment of DHA suppresses EGFR-mediated phenotypes by reducing EGFR nanocluster formation across a variety of in vitro and in vivo models.
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影响因子：
11.2
作者：
Fuentes NR;Mlih M;Barhoumi R;Fan YY;Hardin P;Steele TJ;Behmer S;Prior IA;Karpac J;Chapkin RS
通讯作者：
Chapkin RS
DOI：
10.1016/j.bbamem.2017.03.014
发表时间：
2017-09
期刊：
Biochimica et biophysica acta. Biomembranes
影响因子：
--
作者：
Fuentes NR;Salinas ML;Kim E;Chapkin RS
通讯作者：
Chapkin RS
影响因子：
--
作者：
Cho, Kwang-Jin;Hancock, John F
通讯作者：
Hancock, John F
影响因子：
3.4
作者：
Dinic, Jelena;Ashrafzadeh, Parham;Parmryd, Ingela
通讯作者：
Parmryd, Ingela
影响因子：
7.3
作者：
Alvarez-Guaita, Anna;Vila de Muga, Sandra;Rentero, Carles
通讯作者：
Rentero, Carles