Chrysin inhibited tumor glycolysis and induced apoptosis in hepatocellular carcinoma by targeting hexokinase-2

Dong Xu,Junzhe Jin,Hao Yu,Honglei Jiang,Zheming Zhao,Chundong Zhang,Dongyan Ma

doi:10.1186/s13046-017-0514-4

Abstract

BackgroundHexokinase-2(HK-2) plays dual roles in glucose metabolism and mediation of cell apoptosis, making it an attractive target for cancer therapy. Chrysin is a natural flavone found in plant extracts which are widely used as herb medicine in China. In the present study, we investigated the antitumor activity of chrysin against hepatocellular carcinoma (HCC) and the role of HK-2 played for chrysin to exert its function.MethodsThe expression of HK-2 in HCC cell line and tumor tissue was examined by western blotting and immunohistochemistry staining. The activities of chrysin against HCC cell proliferation and tumor glycolysis were investigated. Chrysin-induced apoptosis was analyzed by flow cytometry. The effect of chrysin on HK-2 expression and the underlying mechanisms by which induced HCC cell apoptosis were studied. In HK-2 exogenous overexpression cell, the changes of chrysin-induced cell apoptosis and glycolysis suppression were investigated. HCC cell xenograft model was used to confirm the antitumor activity of chrysin in vivo and the effect on HK-2 was tested in chrysin-treated tumor tissue.ResultsIn contrast with normal cell lines and tissue, HK-2 expression was substantially elevated in the majority of tested HCC cell lines and tumor tissue. Owing to the decrease of HK-2 expression, glucose uptake and lactate production in HCC cells were substantially inhibited after exposure to chrysin. After chrysin treatment, HK-2 which combined with VDAC-1 on mitochondria was significantly declined, resulting in the transfer of Bax from cytoplasm to mitochondria and induction of cell apoptosis. Chrysin-mediated cell apoptosis and glycolysis suppression were dramatically impaired in HK-2 exogenous overexpression cells. Tumor growth in HCC xenograft models was significantly restrained after chrysin treatment and significant decrease of HK-2 expression was observed in chrysin-treated tumor tissue.ConclusionThrough suppressing glycolysis and inducing apoptosis in HCC, chrysin, or its derivative has a promising potential to be a novel therapeutic for HCC management, especially for those patients with high HK-2 expression.

Highlights

Hexokinase-2(HK-2) plays dual roles in glucose metabolism and mediation of cell apoptosis, making it an attractive target for cancer therapy
HK-2 was highly expressed in hepatocellular carcinoma (HCC) cell lines and tumor tissue First, the expression of HK-2 was assessed by western blotting in six HCC cell lines
These results suggested that HK-2 might have a role in HCC development

Summary

Introduction

Hexokinase-2(HK-2) plays dual roles in glucose metabolism and mediation of cell apoptosis, making it an attractive target for cancer therapy. Various regulatory pathways involved in the conversion from the Krebs cycle to tumor glycolysis have been well investigated, HKs were considered to be one of the most important effectors [4, 5]. Localization to the outer membrane of mitochondria confers HK-2 the advantage to escape product inhibition and gain preferential access to ATP in mitochondrion [6]. Among these different HKs, HK-2 is found to be expressed of high rate in malignant tumors and plays a key role in the development of Warburg phenotype. Overexpression of HK-2 was observed in various cancers, such as gastric [7], ovarian [8], breast cancer [9], cervical carcinoma [10], esophageal adenocarcinoma [11] and nasopharyngeal carcinoma [12]

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Discussion

Conclusion