School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, PR China; National Demonstration Center for Experimental Ethnopharmacology Education, South-Central University for Nationalities, Wuhan, 430074, PR China.
School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, PR China; National Demonstration Center for Experimental Ethnopharmacology Education, South-Central University for Nationalities, Wuhan, 430074, PR China.
Food Chem Toxicol. 2018 Nov;121:156-165. doi: 10.1016/j.fct.2018.08.030. Epub 2018 Aug 29.
Dauricine (Dau) is a natural alkaloid exhibiting anti-proliferative activity against several different types of malignant cell. However, effects of Dau on hepatocellular carcinoma (HCC) cells and the underlying molecular mechanisms have remained to be fully elucidated. In this study, we found that Dau elevated the sensitivities of HCC cells to chemotherapeutic reagents, including cisplatin, sorafenib, and isoliensinine. Moreover, Dau promoted apoptosis of HCC cells triggered by these chemotherapeutic reagents. Consistently, in a xenograft mouse model, Dau sensitized HCC cells to sorafenib. In HCC cells, Dau dose-dependently inhibited glucose glycolysis and increased oxidative phosphorylation. Mechanistically, Dau downregulated the expression of hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2). HK2 and PKM2 can be directly targeted by miR-199a. Dau dose-dependently increased miR-199a expression in HCC cells. Transfection of anti-miR-199a abrogated Dau-mediated suppression of HK2 and PKM2. Dau-induced metabolic shift was thereby severely crippled by anti-miR-199a. In addition, the incremental activity of Dau on sorafenib sensitivity of HCC cells was diminished in response to the transfection of anti-miR-199a. Taken together, our findings provided novel insights into the impact of Dau on HCC cells and supported considering Dau as an adjuvant reagent in the clinical treatment of HCC.
道春碱（Dau）是一种天然生物碱，对多种恶性细胞具有抗增殖活性。然而，道春碱对肝癌（HCC）细胞的作用及其潜在的分子机制仍有待充分阐明。在这项研究中，我们发现道春碱提高了 HCC 细胞对化疗药物（包括顺铂、索拉非尼和异莲心碱）的敏感性。此外，道春碱促进了这些化疗药物引发的 HCC 细胞凋亡。一致的是，在异种移植小鼠模型中，道春碱使 HCC 细胞对索拉非尼敏感。在 HCC 细胞中，道春碱剂量依赖性地抑制葡萄糖糖酵解并增加氧化磷酸化。在机制上，道春碱下调了己糖激酶 2（HK2）和丙酮酸激酶 M2（PKM2）的表达。HK2 和 PKM2 可以被 miR-199a 直接靶向。道春碱剂量依赖性地增加 HCC 细胞中的 miR-199a 表达。转染抗 miR-199a 可消除道春碱对 HK2 和 PKM2 的抑制作用。因此，抗 miR-199a 严重削弱了道春碱引起的代谢转变。此外，在转染抗 miR-199a 后，道春碱对 HCC 细胞索拉非尼敏感性的增效作用减弱。综上所述，我们的研究结果为道春碱对 HCC 细胞的影响提供了新的见解，并支持将道春碱作为 HCC 临床治疗的辅助试剂。
