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      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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          Abstract

          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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          Most cited references41

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          On the origin of cancer cells.

          O WARBURG (1956)
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            TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis

            The p53 tumor-suppressor protein prevents cancer development through various mechanisms, including the induction of cell-cycle arrest, apoptosis, and the maintenance of genome stability. We have identified a p53-inducible gene named TIGAR (TP53-induced glycolysis and apoptosis regulator). TIGAR expression lowered fructose-2,6-bisphosphate levels in cells, resulting in an inhibition of glycolysis and an overall decrease in intracellular reactive oxygen species (ROS) levels. These functions of TIGAR correlated with an ability to protect cells from ROS-associated apoptosis, and consequently, knockdown of endogenous TIGAR expression sensitized cells to p53-induced death. Expression of TIGAR may therefore modulate the apoptotic response to p53, allowing survival in the face of mild or transient stress signals that may be reversed or repaired. The decrease of intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic damage.
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              p53 regulates mitochondrial respiration.

              The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways. We identify Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the cytochrome c oxidase (COX) complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. That SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect and offers new clues as to how p53 might affect aging and metabolism.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                10 April 2018
                10 April 2018
                : 9
                : 27
                : 18949-18969
                Affiliations
                1 Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 302, Taiwan
                2 Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
                3 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
                4 Department of Surgery, Chi Mei Foundation Medical Centre, Tainan 710, Taiwan
                5 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
                6 Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
                7 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
                8 Department of Paediatrics, Chi Mei Foundation Medical Centre, Tainan 710, Taiwan
                9 Department of Neurology and Occupational Medicine, Chi Mei Foundation Medical Centre, Tainan 710, Taiwan
                10 Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital–Kaohsiung Medical Center, Kaohsiung 833, Taiwan
                11 Department of Surgery, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
                Author notes
                Correspondence to: Wen-Tsan Chang, wtchang@ 123456mail.ncku.edu.tw
                [*]

                These authors have contributed equally to this work

                Article
                24855
                10.18632/oncotarget.24855
                5922369
                f693f99e-3df4-4ecd-8189-c2d1e7877999
                Copyright: © 2018 Tseng et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 September 2017
                : 27 February 2018
                Categories
                Research Paper

                Oncology & Radiotherapy
                glycolysis,hexokinase 1 (hk1),hexokinase 2 (hk2),warburg effect,tumor metastasis

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