N-Arachidonoyl Dopamine Inhibits NRAS Neoplastic Transformation by Suppressing Its Plasma Membrane Translocation
N-Arachidonoyl Dopamine Inhibits NRAS Neoplastic Transformation by Suppressing Its Plasma Membrane Translocation
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DOI：
10.1158/1535-7163.mct-16-0419
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发表时间：
2016-10
影响因子：
5.7
通讯作者：
Min Wu;Jinyan Huang;Jianming Zhang;C. Benes;B. Jiao;R. Ren
中科院分区：
文献类型：
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作者：
Min Wu;Jinyan Huang;Jianming Zhang;C. Benes;B. Jiao;R. Ren
RAS致癌突变在人类癌症中很常见，但RAS蛋白很难定位。我们试图通过一种独特的机制来确定阻断RAS致癌信号的药理学药物。由于RAS蛋白的生物活性依赖于脂质修饰，并且RAS调节癌细胞中的脂质代谢，因此我们使用RAS特异性细胞活力测定筛选了具有生物活性的脂质文库。我们报道了一类新的RAS转化抑制剂的发现。以内源性大麻素n -花生四烯酰基多巴胺（NADA）为代表的一类化合物可以诱导细胞肿瘤，而不依赖于其参与大麻素受体的能力。进一步分析表明，NADA在抑制NRAS转化和信号传导方面比KRAS4B更活跃。在机制上，NADA阻断NRAS的质膜易位，但不阻断KRAS4B的质膜易位。此外，NADA还能抑制致癌基因KRAS4A的质膜易位和肿瘤转化。有趣的是，NADA还以棕榈酰化依赖的方式将细胞质NRAS重新分配到高尔基体。结果表明，NADA通过靶向一种新的分子过程抑制NRAS和KRAS4A质膜易位。这项新发现将有助于开发针对多种人类癌症的新型靶向疗法。巨蟹座；16 (1);57 - 67。AACR©2016。
RAS oncogenic mutations are common in human cancers, but RAS proteins have been difficult to target. We sought to identify pharmacological agents to block RAS oncogenic signaling by a distinct mechanism. Because the biological activity of RAS proteins relies upon lipid modifications and RAS regulates lipid metabolisms in cancer cells, we screened a bioactive lipid library using a RAS-specific cell viability assay. We report the discovery of a new class of inhibitors for RAS transformation. Compounds in the class represented by endocannabinoid N-arachidonoyl dopamine (NADA) can induce cell oncosis, independent of its ability to engage cannabinoid receptors. Further analyses show that NADA is more active in inhibiting the NRAS transformation and signaling than that of KRAS4B. Mechanistically, NADA blocks the plasma membrane translocation of NRAS, but not that of KRAS4B. In addition, NADA inhibits plasma membrane translocation and neoplastic transformation of oncogenic KRAS4A. Interestingly, NADA also redistributes the cytoplasmic NRAS to the Golgi apparatus in a palmitoylation-dependent manner. The results indicate that NADA inhibits NRAS and KRAS4A plasma membrane translocation by targeting a novel molecular process. The new findings would help to develop novel targeted therapies for a broad range of human cancers. Mol Cancer Ther; 16(1); 57–67. ©2016 AACR.