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By blocking hexokinase-2 phosphorylation, limonin suppresses tumor glycolysis and induces cell apoptosis in hepatocellular carcinoma.

Abstract：

Introduction:The purpose of present study was to investigate the effect of limonin on tumor glycolysis and the underlying mechanisms in hepatocellular carcinoma (HCC). Methods:Cell proliferation and colony formation assays were performed to evaluate the potency of limonin against HCC cells in vitro. The glucose consumption and lactate production after limonin treatment was determined. The effect of limonin on hexokinase-2 (HK-2) activity was assessed and the mitochondrial location of HK-2 was studied by immunoprecipitation. Cell apoptosis and protein expression were detected by flow cytometry and western blotting respectively. Protein overexpression by plasmid transfection was adopted to investigate the molecular mechanisms. Results:HCC proliferation and colony formation were inhibited by limonin in vitro. With the suppression of HK-2 activity, the glycolytic level in HCC cells was substantially reduced, which was evidenced by the decrease of glucose consumption and lactate production. The phosphorylation of HK-2 was substantially inhibited by limonin, which resulted in the disassociation of HK-2 from mitochondria. Due to the reduction of HK-2 in mitochondria, increasing Bax were shifted to the mitochondria and gave rise to the release of cytochrome C, which induced HCC cells to subject to mitochondria-mediated apoptosis. Mechanism investigations revealed that the decrease of HK-2 phosphorylation was mainly due to the inhibition of Akt activity. In Akt exogenously overexpressed HCC cells, limonin-mediated cell proliferation inhibition, glycolysis suppression and apoptosis induction were significantly impaired. Conclusion:Limonin inhibited the tumor glycolysis in hepatocellular carcinoma by suppressing HK-2 activity, and the suppression of HK-2 was closely related to the decrease of Akt activity.

journal_name

Onco Targets Ther

journal_title

OncoTargets and therapy

authors

Yao J,Liu J,Zhao W

doi

10.2147/OTT.S165220

subject

Has Abstract

pub_date

2018-07-03 00:00:00

pages

3793-3803

issn

1178-6930

pii

ott-11-3793

journal_volume

pub_type

杂志文章

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By blocking hexokinase-2 phosphorylation, limonin suppresses tumor glycolysis and induces cell apoptosis in hepatocellular carcinoma.