By reducing hexokinase 2, resveratrol induces apoptosis in HCC cells addicted to aerobic glycolysis and inhibits tumor growth in mice.

Weiqi Dai,Huerxidan Abudumijiti,Huawei Zhang,Rongxia Chen,Zheng Zhou,Chengfen Wang,Lei He,Yingqun Zhou,Jingjing Li,Wenxia Lu,Sainan Li,Jianrong Wang,Ling Xu,Chuanyong Guo,Yujing Xia,Yuqing Zhou,Kan Chen,Rong Zhu,Yuanyuan Zheng,Qin Yin,Jing Yang,Rong Zhang,Tong Liu,Fan Wang,Liqun Zhou ,Jie Lü

doi:10.18632/oncotarget.3800

Abstract

Cancer cells exhibit an altered metabolic phenotype known as the aerobic glycolysis. The expression of HK2 changes the metabolic phenotype of cells to support cancerous growth. In the present study, we investigated the inhibitory effect of resveratrol on HK2 expression and hepatocellular carcinoma (HCC) cell glycolysis. Aerobic glycolysis was observed in four HCC cell lines compared to the normal hepatic cells. Resveratrol sensitized aerobic glycolytic HCC cells to apoptosis, and this effect was attenuated by glycolytic inhibitors. The induction of mitochondrial apoptosis was associated with the decrease of HK2 expression by resveratrol in HCC cells. In addition, resveratrol enhanced sorafenib induced cell growth inhibition in aerobic glycolytic HCC cells. Combination treatment with both reagents inhibited the growth and promoted apoptosis of HCC-bearing mice. The reduction of HK2 by resveratrol provides a new dimension to clinical HCC therapies aimed at preventing disease progression.

Highlights

One of the metabolic features of tumor cells is the aerobic glycolysis, by which tumor cells, even in the presence of sufficient oxygen, activate glycolysis and convert pyruvate to lactate acid rather than totally oxidizing it by Krebs cycle [1]
Glucose uptake was slightly higher in SMMC-7721 and HepG2 cells than in QSG-7701 and LO2 cells, whereas Huh-7 cells showed no glucose uptake changes in lactate production and glucose uptake. These results indicate that hepatocellular carcinoma (HCC) cell lines show an increased rate of aerobic glycolysis compared to healthy cells
We showed that the aerobic glycolysis, which is characterized by enhanced lactate production and glucose uptake, occurred in the majority of the HCC cell lines examined

Summary

Introduction

One of the metabolic features of tumor cells is the aerobic glycolysis, by which tumor cells, even in the presence of sufficient oxygen, activate glycolysis and convert pyruvate to lactate acid rather than totally oxidizing it by Krebs cycle [1]. Glycolysis, the major pathway for energy production, is pivotal for the survival and growth of cancer cells [2]. The mechanisms underlying the shift from the Krebs cycle to glycolysis in cancer cells are well studied, and it is believed that hexokinase 2 (HK2) contributes to this process [3]. Disruption of the binding of HK with VDAC causes mitochondrial dysfunction and induces cell death [5]. The upregulated mitochondria-bound HK2 in tumor cells, as well as the high glucose phosphorylation activity, promote tumor cell proliferation and survival by enhancing energy production and the escape from mitochondriaassociated cell death [7]. HK2 in particular, is regarded as a potential target for anticancer therapy, and the screening of drugs that suppress HK2 expression and prevent metabolic transformation becomes meaningful [5]

Methods

Results

Conclusion