Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance.
Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance.
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DOI：
10.1096/fj.201601248r
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发表时间：
2017-05
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影响因子：
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通讯作者：
Voest EE
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作者：
Houthuijzen JM;Oosterom I;Hudson BD;Hirasawa A;Daenen LGM;McLean CM;Hansen SVF;van Jaarsveld MTM;Peeper DS;Jafari Sadatmand S;Roodhart JML;van de Lest CHA;Ulven T;Ishihara K;Milligan G;Voest EE
虽然化疗旨在根除肿瘤细胞，但它对正常组织也有显着影响。铂诱导的脂肪酸16：4（n-3）（十六碳-4，7，10，13-四烯酸）诱导对广泛的DNA损伤化疗药物的全身性耐药性。我们发现16：4（n-3）通过激活脾F4/80+/CD 11 blow巨噬细胞发挥其作用，这导致产生化学保护性溶血磷脂酰胆碱（LPC）。药理学研究以及表达模式分析确定F4/80+/CD 11巨噬细胞上的GPR 120为16：4（n-3）的相关受体。使用GPR 120缺陷小鼠脾细胞的研究证实了这一结论。16：4（n-3）-GPR 120轴的激活导致这些脾巨噬细胞中cPLA 2活性的增强和抵抗诱导脂质介质溶血磷脂酰胆碱（24：1）的分泌。这些研究确定了GPR 120的一种新的和意想不到的功能，并表明该受体的拮抗剂可能是限制化疗耐药性发展的有效药物。Houthuijzen，J. M.，奥斯特罗姆岛哈德逊，B。D、Hirasawa，A.，达嫩湖G. M.，姆克林角M.，汉森，S. V.F.，货车Jaarsveld，M. T. M.，Peeper，D.美国，Jafari Sadatmand，S.，鲁德哈特L.，货车德莱斯特角H.一、Ulven，T.，石原，K.，米利根，G.，Voest，E. E.脂肪酸16：4（n-3）刺激脾巨噬细胞中GPR 120诱导的信号级联反应，以促进化疗耐药性。
Although chemotherapy is designed to eradicate tumor cells, it also has significant effects on normal tissues. The platinum-induced fatty acid 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid) induces systemic resistance to a broad range of DNA-damaging chemotherapeutics. We show that 16:4(n-3) exerts its effect by activating splenic F4/80+/CD11blow macrophages, which results in production of chemoprotective lysophosphatidylcholines (LPCs). Pharmacologic studies, together with analysis of expression patterns, identified GPR120 on F4/80+/CD11blow macrophages as the relevant receptor for 16:4(n-3). Studies that used splenocytes from GPR120-deficient mice have confirmed this conclusion. Activation of the 16:4(n-3)-GPR120 axis led to enhanced cPLA2 activity in these splenic macrophages and secretion of the resistance-inducing lipid mediator, lysophosphatidylcholine(24:1). These studies identify a novel and unexpected function for GPR120 and suggest that antagonists of this receptor might be effective agents to limit development of chemotherapy resistance.—Houthuijzen, J. M., Oosterom, I., Hudson, B. D., Hirasawa, A., Daenen, L. G. M., McLean, C. M., Hansen, S. V. F., van Jaarsveld, M. T. M., Peeper, D. S., Jafari Sadatmand, S., Roodhart, J. M. L., van de Lest, C. H. A., Ulven, T., Ishihara, K., Milligan, G., Voest, E. E. Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance.