Cell Metabolomics Reveals Berberine-Inhibited Pancreatic Cancer Cell Viability and Metastasis by Regulating Citrate Metabolism
Cell Metabolomics Reveals Berberine-Inhibited Pancreatic Cancer Cell Viability and Metastasis by Regulating Citrate Metabolism
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DOI：
10.1021/acs.jproteome.0c00394
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发表时间：
2020-09-04
影响因子：
4.4
通讯作者：
Lu, Haitao
中科院分区：
文献类型：
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作者：
Liu, Jingjing;Luo, Xialin;Lu, Haitao
胰腺癌（PC）正在成为最致命的癌症之一，由于其致病潜伏期和临床上缺乏有效的药物，其死亡率在世界范围内最高。考虑到癌细胞以大量代谢为代价进行增殖和分化，如糖酵解失调和线粒体损伤诱导的TCA循环异常所示，我们使用细胞代谢组学方法研究了小檗碱（BBR）在胰腺癌中的治疗能力。表型分析显示BBR在PC细胞活力和转移中具有显著的抑制作用。此外，一项精确靶向代谢组学分析表明，BBR严重失调PC细胞的能量代谢，基于成像的表型观察表明，PC细胞线粒体在BBR处理后明显受损。值得注意的是，柠檬酸盐代谢和运输在细胞线粒体中的显着影响BBR，这导致通过调节ACLY，ACO1和SLC25A1的生物合成的定义的脂肪酸（FA）的阻滞。因此，BBR可能通过靶向柠檬酸盐代谢来调节FA对PC细胞增殖和转移的调节作用。总的来说，我们的体外数据初步揭示了BBR通过靶向柠檬酸盐代谢来治疗胰腺癌的潜力，柠檬酸盐可能成为药物开发和治疗PC的新靶点，但后续还需要进一步的实验验证。此外，我们的研究表明，细胞代谢组学方法适用于快速探索天然产物的生化功能的能力。
Pancreatic cancer (PC) is becoming one of the deadliest cancers, with mortality among the highest worldwide because of its pathogenic latency and the lack of efficient drugs in the clinic. Considering that cancer cells undergo proliferation and differentiation at substantial metabolic costs, as indicated by dysregulated glycolysis and an abnormal TCA cycle induced by mitochondrial damage, we investigated the therapeutic capacity of berberine (BBR) in pancreatic cancer using a cell metabolomics method. A phenotypic assay revealed the significant inhibitory role of BBR in PC cell viability and metastasis. In addition, a precisiontargeted metabolome assay showed that BBR profoundly dysregulated the energy metabolism of PC cells, and phenotypic observations based on imaging indicated that PC cell mitochondria were markedly damaged after BBR treatment. Notably, citrate metabolism and transportation in cell mitochondria were significantly influenced by BBR, which led to the blocked biosynthesis of the defined fatty acids (FAs) through the regulation of ACLY, ACO1, and SLC25A1. Therefore, the regulatory effects of FAs on PC cell proliferation and metastasis may be regulated by BBR through targeting citrate metabolism. Collectively, our in vitro data preliminarily reveals the therapeutic potential of BBR against pancreatic cancer by targeting citrate metabolism, citrate might be a new target for drug development and the treatment against PC, but further experimental verification will be required subsequently. Moreover, our study demonstrated that the cell metabolomics method pertains to the capacity to rapidly explore biochemical functions of natural products.