Echinatin suppresses esophageal cancer tumor growth and invasion through inducing AKT/mTOR-dependent autophagy and apoptosis
Echinatin suppresses esophageal cancer tumor growth and invasion through inducing AKT/mTOR-dependent autophagy and apoptosis
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Echinatin 通过诱导 AKT/mTOR 依赖性自噬和细胞凋亡抑制食管癌肿瘤生长和侵袭
DOI：
10.1038/s41419-020-2730-7
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发表时间：
2020-07-13
影响因子：
9
通讯作者：
Xu, Wen Wen
中科院分区：
文献类型：
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作者：
Hong, Pan;Liu, Qin-Wen;Xu, Wen Wen
食管鳞状细胞癌是最常见的恶性肿瘤之一，生存率低。因此，寻找具有良好稳定性和安全性的新型有效药物，为临床治疗提供新的思路和方法是当务之急。本研究旨在从429种天然产物组成的化合物库中筛选潜在的抗癌药物。Echinatin是一种从中药甘草菲施中分离得到的化合物，能显著诱导食管鳞癌细胞凋亡，抑制其增殖和集落形成能力。共聚焦荧光显微镜数据显示，棘球蛋白显着诱导ESCC细胞自噬，自噬抑制剂巴菲霉素A1减弱棘球蛋白对细胞活力和凋亡的抑制作用。RNA测序结合生物信息学分析和一系列功能测定揭示了棘蛋白通过灭活AKT/mTOR信号通路诱导细胞凋亡和自噬，而AKT的组成性激活则显著消除了这些作用。此外，我们证明了棘球蛋白在肿瘤异种移植模型中具有显著的抗肿瘤作用，并以剂量依赖性方式显著抑制ESCC细胞的细胞迁移和侵袭能力。我们的研究结果提供了第一个证据表明，棘球蛋白可能是一种新的治疗策略，用于治疗食管鳞癌。
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with poor survival. It is urgent to search for new efficient drugs with good stability and safety for clinical therapy. This study aims to identify potential anticancer drugs from a compound library consisting of 429 natural products. Echinatin, a compound isolated from the Chinese herbGlycyrrhiza uralensis Fisch, was found to markedly induce apoptosis and inhibit proliferation and colony-formation ability in ESCC. Confocal fluorescence microscopy data showed that echinatin significantly induced autophagy in ESCC cells, and autophagy inhibitor bafilomycinA1 attenuated the suppressive effects of echinatin on cell viability and apoptosis. Mechanistically, RNA sequencing coupled with bioinformatics analysis and a series of functional assays revealed that echinatin induced apoptosis and autophagy through inactivation of AKT/mTOR signaling pathway, whereas constitutive activation of AKT significantly abrogated these effects. Furthermore, we demonstrated that echinatin had a significant antitumor effect in the tumor xenograft model and markedly suppressed cell migration and invasion abilities of ESCC cells in a dose-dependent manner. Our findings provide the first evidence that echinatin could be a novel therapeutic strategy for treating ESCC.