PMID- 29721175 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20191120 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 9 IP - 27 DP - 2018 Apr 10 TI - The decrease of glycolytic enzyme hexokinase 1 accelerates tumor malignancy via deregulating energy metabolism but sensitizes cancer cells to 2-deoxyglucose inhibition. PG - 18949-18969 LID - 10.18632/oncotarget.24855 [doi] AB - 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. FAU - Tseng, Po-Lin AU - Tseng PL AD - Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 302, Taiwan. AD - Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan. FAU - Chen, Chih-Wei AU - Chen CW AD - Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. AD - Department of Surgery, Chi Mei Foundation Medical Centre, Tainan 710, Taiwan. AD - Department 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. FAU - Hu, Keng-Hsun AU - Hu KH AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. FAU - Cheng, Hung-Chi AU - Cheng HC AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. AD - Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. FAU - Lin, Yuan-Ho AU - Lin YH AD - Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. FAU - Tsai, Wen-Hui AU - Tsai WH AD - Department of Paediatrics, Chi Mei Foundation Medical Centre, Tainan 710, Taiwan. FAU - Cheng, Tain-Junn AU - Cheng TJ AD - Department 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. AD - Department of Neurology and Occupational Medicine, Chi Mei Foundation Medical Centre, Tainan 710, Taiwan. FAU - Wu, Wei-Hsuan AU - Wu WH AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. FAU - Yeh, Chin-Wei AU - Yeh CW AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. FAU - Lin, Chin-Chih AU - Lin CC AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. FAU - Tsai, Hui-Ju AU - Tsai HJ AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. FAU - Chang, Hao-Chun AU - Chang HC AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. FAU - Chuang, Jiin-Haur AU - Chuang JH AD - Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung 833, Taiwan. FAU - Shan, Yan-Shen AU - Shan YS AD - Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. AD - Department of Surgery, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. FAU - Chang, Wen-Tsan AU - Chang WT AD - Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. AD - Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. AD - Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. LA - eng PT - Journal Article DEP - 20180410 PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 PMC - PMC5922369 OTO - NOTNLM OT - Warburg effect OT - glycolysis OT - hexokinase 1 (HK1) OT - hexokinase 2 (HK2) OT - tumor metastasis COIS- CONFLICTS OF INTEREST The authors declare no competing financial interests. EDAT- 2018/05/04 06:00 MHDA- 2018/05/04 06:01 PMCR- 2018/04/10 CRDT- 2018/05/04 06:00 PHST- 2017/09/21 00:00 [received] PHST- 2018/02/27 00:00 [accepted] PHST- 2018/05/04 06:00 [entrez] PHST- 2018/05/04 06:00 [pubmed] PHST- 2018/05/04 06:01 [medline] PHST- 2018/04/10 00:00 [pmc-release] AID - 24855 [pii] AID - 10.18632/oncotarget.24855 [doi] PST - epublish SO - Oncotarget. 2018 Apr 10;9(27):18949-18969. doi: 10.18632/oncotarget.24855. eCollection 2018 Apr 10.