N‐acyl dopamines (NADAs) are bioactive lipids of the endovanilloid family with known cytotoxicity for the cancer cells; however, the available data on the participation of the endovanilloids in epithelial–mesenchymal transition (EMT) and cancer stemness are controversial. This study unveils the inhibitory role of N‐arachidonoyl dopamine (AA‐DA), a typical representative of the NADA family, in breast cancer cell migration, EMT, and stemness. AA‐DA treatment also led to a decrease in cholesterol biosynthesis gene expressions, and addition of exogenous cholesterol reverted these AA‐DA‐mediated inhibitory effects. Notably, AA‐DA treatment inhibited the key regulatory gene of the cholesterol biosynthesis pathway, sterol regulatory element‑binding protein 1 (SREBP1), with concurrent repression of the endoplasmic reticulum kinase 1/2 (ERK1/2) pathway. Furthermore, U0126, an ERK inhibitor, inhibited SREBP1 and decreased cellular cholesterol level, unwinding the molecular mechanism behind AA‐DA‐mediated anticancer activity. Thus, we, for the first time, revealed that AA‐DA counteracts breast cancer EMT via inhibition of ERK signaling and cholesterol content.

中文翻译：

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N-花生四烯酸多巴胺通过ERK信号传导抑制乳腺癌细胞上皮-间质转化并降低细胞胆固醇

N-酰基多巴胺（NADAs）是vanvanilloidid家族的生物活性脂质，对癌细胞具有已知的细胞毒性。但是，有关内淋巴管细胞参与上皮-间质转化（EMT）和癌干性的现有数据存在争议。这项研究揭示了N的抑制作用花生四烯酸多巴胺（AA-DA）是NADA家族的典型代表，在乳腺癌细胞迁移，EMT和干性方面具有重要意义。AA-DA处理还导致胆固醇生物合成基因表达下降，外源胆固醇的添加逆转了这些AA-DA介导的抑制作用。值得注意的是，AA-DA处理抑制了胆固醇生物合成途径的关键调节基因固醇调节元素结合蛋白1（SREBP1），同时抑制了内质网激酶1/2（ERK1 / 2）通路。此外，ERK抑制剂U0126抑制SREBP1并降低细胞胆固醇水平，从而消除了AA-DA介导的抗癌活性背后的分子机制。因此，我们首次揭示了AA-DA通过抑制ERK信号传导和胆固醇含量来抵消乳腺癌EMT。