The decrease of glycolytic enzyme hexokinase 1 accelerates tumor malignancy via deregulating energy metabolism but sensitizes cancer cells to 2-deoxyglucose inhibition
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Po-Lin Tseng1,2,*, Chih-Wei Chen3,4,5,*, Keng-Hsun Hu6,*, Hung-Chi Cheng6,7, Yuan-Ho Lin7, Wen-Hui Tsai8, Tain-Junn Cheng5,9, Wei-Hsuan Wu6, Chin-Wei Yeh6, Chin-Chih Lin6, Hui-Ju Tsai6, Hao-Chun Chang6, Jiin-Haur Chuang10, Yan-Shen Shan3,11 and Wen-Tsan Chang3,6,7
1Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 302, Taiwan
2Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
3Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
4Department of Surgery, Chi Mei Foundation Medical Centre, Tainan 710, Taiwan
5Department of Occupational Safety and Health/Institute of Industrial Safety and Disaster Prevention, College of Sustainable Environment, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
6Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
7Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
8Department of Paediatrics, Chi Mei Foundation Medical Centre, Tainan 710, Taiwan
9Department of Neurology and Occupational Medicine, Chi Mei Foundation Medical Centre, Tainan 710, Taiwan
10Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital–Kaohsiung Medical Center, Kaohsiung 833, Taiwan
11Department of Surgery, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
*These authors have contributed equally to this work
Wen-Tsan Chang, email: [email protected]
Keywords: glycolysis; hexokinase 1 (HK1); hexokinase 2 (HK2); Warburg effect; tumor metastasis
Received: September 21, 2017 Accepted: February 27, 2018 Published: April 10, 2018
Malignant tumors often display an aberrant energy metabolism that relies primarily on glycolysis to produce adenosine triphosphate (ATP) the so-called Warburg effect or aerobic glycolysis. Thus, the elucidation of this energetic alteration in malignant tumors is important in the search for more effective therapeutics against malignant cancers, the most deadly human disease. To investigate whether attenuated glycolytic activity modulates tumor progression, the effects of silencing the first and rate-limiting glycolytic enzyme hexokinase (HK) isozymes HK1 and HK2 were examined. There was an inverse correlation between the expression of HK1 and HK2 in human cancer cells. In cervical carcinoma cells, the HK1 but not HK2 knockdown induced a phenotypic change characteristic of epithelial-mesenchymal transition, which accelerated tumor growth and metastasis both in vitro and in vivo analyses. Notably, the silencing of HK1 disrupted aerobic respiration and increased glycolysis, but it had no effect on ATP generation. These metabolic changes were associated with higher HK2 and lactate dehydrogenase 1 expression but a lower citrate synthase level. Particularly, the HK1 knockdown induced aberrant energy metabolism that was almost recapitulated by HK2 overexpression. Moreover, the HK1-silenced cells showed strong glucose-dependent growth and 2-deoxyglucose (2-DG) induced cell proliferation inhibition. These results clearly indicate that the silencing of HK1, but not HK2, alters energy metabolism and induces an EMT phenotype, which enhances tumor malignancy, but increases the susceptibility of cancer cells to 2-DG inhibition. In addition, this work also suggests that the glycolytic inhibitors should be used only to treat cancers with elevated glycolytic activity.
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