Xu Dong, Jin Junzhe, Yu Hao, Zhao Zheming, Ma Dongyan, Zhang Chundong, Jiang Honglei
Department of General Surgery, the fourth affiliated hospital of China Medical University, The No.4 Chongshan east road Huanggu District, Shenyang, 110032, LiaoNing, China.
J Exp Clin Cancer Res. 2017 Mar 20;36(1):44. doi: 10.1186/s13046-017-0514-4.
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.
己糖激酶-2（HK-2）在葡萄糖代谢和细胞凋亡介导中发挥双重作用，使其成为癌症治疗的一个有吸引力的靶点。白杨素是一种天然黄酮，存在于植物提取物中，在中国被广泛用作草药。在本研究中，我们研究了白杨素对肝细胞癌（HCC）的抗肿瘤活性以及HK-2在白杨素发挥其功能中所起的作用。
通过蛋白质免疫印迹法和免疫组织化学染色检测HK-2在肝癌细胞系和肿瘤组织中的表达。研究了白杨素对肝癌细胞增殖和肿瘤糖酵解的活性。通过流式细胞术分析白杨素诱导的细胞凋亡。研究了白杨素对HK-2表达的影响以及诱导肝癌细胞凋亡的潜在机制。在HK-2外源性过表达细胞中，研究了白杨素诱导的细胞凋亡和糖酵解抑制的变化。使用肝癌细胞异种移植模型在体内证实白杨素的抗肿瘤活性，并在白杨素处理的肿瘤组织中检测对HK-2的影响。
与正常细胞系和组织相比，大多数测试的肝癌细胞系和肿瘤组织中HK-2表达显著升高。由于HK-2表达降低，暴露于白杨素后肝癌细胞中的葡萄糖摄取和乳酸产生显著受到抑制。白杨素处理后，与线粒体上的电压依赖性阴离子通道1（VDAC-1）结合的HK-2显著下降，导致 Bax 从细胞质转移到线粒体并诱导细胞凋亡。在HK-2外源性过表达细胞中白杨素介导的细胞凋亡和糖酵解抑制显著受损。白杨素处理后，肝癌异种移植模型中的肿瘤生长显著受到抑制，并且在白杨素处理的肿瘤组织中观察到HK-2表达显著降低。
通过抑制肝癌细胞的糖酵解和诱导凋亡，白杨素或其衍生物具有成为肝癌治疗新疗法的潜力，特别是对于那些HK-2高表达的患者。
