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2018 ; 11
(ä): 3793-3803
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By blocking hexokinase-2 phosphorylation, limonin suppresses tumor glycolysis and
induces cell apoptosis in hepatocellular carcinoma
#MMPMID30013360
Yao J
; Liu J
; Zhao W
Onco Targets Ther
2018[]; 11
(ä): 3793-3803
PMID30013360
show ga
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.