Journal
JOURNAL OF HEPATOCELLULAR CARCINOMA
Volume 7, Issue -, Pages 19-31Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/JHC.S237614
Keywords
shikonin; PKM2; glycolysis; apoptosis; proliferation; hepatocellular carcinoma
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Funding
- National Natural Science Foundation of China [81670472, 81700502, 81800538]
- Shanghai Science and Technology Commission Sailing Program [2018YF1420000]
- Shanghai Putuo District Science and Technology Commission Health System Innovation Program [ptkwws201901]
- China Hepatitis Prevention Foundation WBN Liver Disease Research Fund [2019031]
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Objective: Shikonin is a natural product with many activities, including anti-cancer effects. Pyruvate kinase type M2 (PKM2) plays a crucial role in the growth of tumor cells. However, the effect of shikonin on PKM2 in hepatocellular carcinoma (HCC) is unclear. Methods: Cell viability, apoptosis level, glucose uptake, and lactate production were detected in HCC cells. Lentivirus-overexpressed and -shRNA of PKM2 were used to verify the key target of shikonin. A xenograft mouse model was used to detect the efficacy of shikonin and its combination with sorafenib in vivo. Results: Shikonin inhibited proliferation and glycolysis and induced apoptosis in HCC cells. Either PKM2-overexpressed or PKM2-shRNA alleviated or enhanced this effect. The results of CCK-8 showed that shikonin significantly inhibited cell viability of HCC cells. The levels of glucose uptake and lactate production were dramatically decreased by shikonin-treated. Results of flow cytometry and Western blot showed that the levels of apoptosis of HCC cells were significantly increased in a dose-dependent manner after shikonin treatment. In addition, shikonin enhanced the anti-cancer effect of sorafenib in vitro and in vivo. Our results showed that SK combined with sorafenib markedly inhibits tumor growth in HCC-transplanted nude mice compared to SK or sorafenib alone. Conclusion: By inhibiting PKM2, shikonin inhibited proliferation and glycolysis and induced cell apoptosis in HCC cells. The effect of shikonin on tumor cell proliferation, apoptosis and glycolsis will make it promising drug for HCC patients.
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