Shikonin exerts antitumor activity by causing mitochondrial dysfunction in hepatocellular carcinoma through PKM2-AMPK-PGC1α signaling pathway
Shikonin exerts antitumor activity by causing mitochondrial dysfunction in hepatocellular carcinoma through PKM2-AMPK-PGC1α signaling pathway
复制标题
紫草素通过 PKM2-AMPK-PGC1 α 信号通路引起肝细胞癌线粒体功能障碍而发挥抗肿瘤活性
DOI：
10.1139/bcb-2018-0310
复制
发表时间：
2019-08-01
影响因子：
2.9
通讯作者：
Xie, Caifeng
中科院分区：
文献类型：
--
作者：
Liu, Bing;Jin, Jiangbo;Xie, Caifeng
紫草素是从紫草根中分离得到的一种萘醌类化合物，通过不同的分子机制具有广谱的抗肿瘤活性。在本研究中，我们研究了紫草素对肝细胞癌线粒体功能障碍的影响。结果表明，紫草素抑制HCCLM3细胞的增殖、迁移和侵袭，促进细胞凋亡，并呈剂量依赖关系。更重要的是，紫草素通过破坏线粒体膜电位和氧化应激(OS)状态来影响线粒体功能。此外，紫草素还能降低HCCLM3细胞的耗氧率，降低三羧酸循环(TCA循环)所涉及的ATP和代谢物的水平。我们还研究了紫草素作为PKM2的抑制剂调节线粒体功能的分子机制。紫草素降低线粒体中PKM2的表达，并影响其他代谢途径(AMPK和PGC1α途径)，从而加重氧化应激和营养缺乏。我们的结果表明，紫草素通过PKM2-AMPK-PGC1α信号通路在引发线粒体功能障碍中发挥了新的作用，并为肝癌的治疗提供了一种有前景的治疗途径。
Shikonin, a naphthoquinone derivative isolated from the root of Lithospermum erythrorhizon, exhibits broad-spectrum antitumor activity via different molecular mechanisms. In this study, we investigated the effect of shikonin on mitochondrial dysfunction in hepatocellular carcinoma (HCC). Our results showed that shikonin inhibited the proliferation, migration, and invasiveness of HCCLM3 cells, and promoted cell apoptosis in a dose-dependent manner. More importantly, shikonin affected mitochondrial function by disrupting mitochondrial membrane potential and oxidative stress (OS) status. Furthermore, shikonin decreased the oxygen consumption rate of HCCLM3 cells, as well as the levels of ATP and metabolites involved in the tricarboxylic acid cycle (TCA cycle). We also investigated the molecular mechanisms underlying the regulation of mitochondrial function by shikonin as an inhibitor of PKM2. Shikonin decreased the expression of PKM2 in the mitochondria and affected other metabolic pathways (AMPK and PGC1 alpha pathways), which aggravated the oxidative stress and nutrient deficiency. Our results indicate a novel role of shikonin in triggering mitochondria dysfunction via the PKM2-AMPK-PGC1 alpha signaling pathway and provide a promising therapeutic approach for the treatment of HCC.