Dauricine upregulates the chemosensitivity of hepatocellular carcinoma cells: Role of repressing glycolysis via miR-199a:HK2/PKM2 modulation.
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.
['Li|Wei|W|', 'Qiu|Yunhan|Y|', 'Hao|Ji|J|', 'Zhao|Chi|C|', 'Deng|Xukun|X|', 'Shu|Guangwen|G|']
D000332:Aerobiosis D000818:Animals D000970:Antineoplastic Agents D044182:Benzylisoquinolines D006528:Carcinoma, Hepatocellular D002352:Carrier Proteins D045744:Cell Line, Tumor D019008:Drug Resistance, Neoplasm D006019:Glycolysis D006801:Humans D016547:Kinesins D008113:Liver Neoplasms D008565:Membrane Proteins D051379:Mice D008819:Mice, Nude D035683:MicroRNAs D010085:Oxidative Phosphorylation D044005:Tetrahydroisoquinolines D013963:Thyroid Hormones D015854:Up-Regulation
Dauricine Chemosensitivity Hepatocellular carcinoma Glycolysis MiR-199a