By reducing hexokinase 2, resveratrol induces apoptosis in HCC cells addicted to aerobic glycolysis and inhibits tumor growth in mice
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Weiqi Dai1,*, Fan Wang1,*, Jie Lu1,*, Yujing Xia1, Lei He1, Kan Chen1, Jingjing Li1, Sainan Li1, Tong Liu1, Yuanyuan Zheng1, Jianrong Wang1,2, Wenxia Lu1,2, Yuqing Zhou1,3, Qin Yin1,3, Huerxidan Abudumijiti1, Rongxia Chen1, Rong Zhang1,2, Li Zhou1,2, Zheng Zhou1,2, Rong Zhu1,2, Jing Yang1, Chengfen Wang1, Huawei Zhang1,3, Yingqun Zhou1, Ling Xu4 and Chuanyong Guo1
1 Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
2 The First Clinical Medical College of Nanjing Medical University, Nanjing, China
3 The First Affiliated Hospital of Soochow University, Suzhou, China
4 Department of Gastroenterology, Shanghai Tongren Hospital, Jiaotong University of Medicine, Shanghai, China
* These authors have contributed equally to this work
Chuanyong Guo, email:
Ling Xu, email:
Keywords: resveratrol, hexokinase 2, hepatocellular carcinoma, apoptosis
Received: January 21, 2015 Accepted: March 18, 2015 Published: April 12, 2015
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.
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