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



The 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.



In 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.



Through 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.
Department of General Surgery, the fourth affiliated hospital of China Medical University, The No.4 Chongshan east road Huanggu District, Shenyang, 110032, LiaoNing, China.
Dong
D
Xu
Department of General Surgery, the fourth affiliated hospital of China Medical University, The No.4 Chongshan east road Huanggu District, Shenyang, 110032, LiaoNing, China.
Junzhe
J
Jin
Department of General Surgery, the fourth affiliated hospital of China Medical University, The No.4 Chongshan east road Huanggu District, Shenyang, 110032, LiaoNing, China.
Hao
H
Yu
Department of General Surgery, the fourth affiliated hospital of China Medical University, The No.4 Chongshan east road Huanggu District, Shenyang, 110032, LiaoNing, China.
Zheming
Z
Zhao
Department of General Surgery, the fourth affiliated hospital of China Medical University, The No.4 Chongshan east road Huanggu District, Shenyang, 110032, LiaoNing, China.
Dongyan
D
Ma
Department of General Surgery, the fourth affiliated hospital of China Medical University, The No.4 Chongshan east road Huanggu District, Shenyang, 110032, LiaoNing, China.
Chundong
C
Zhang
Department of General Surgery, the fourth affiliated hospital of China Medical University, The No.4 Chongshan east road Huanggu District, Shenyang, 110032, LiaoNing, China. hongleijiang_bio@126.com.
Honglei
H
Jiang
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005419:Flavonoids / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects*; D056945:Hep G2 Cells; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; C043561:chrysin; C000609700:HK2 protein, human; D006593:Hexokinase
Apoptosis; Chrysin; Hepatocellular carcinoma; Hexokinase-2(HK-2); Tumor glycolysis