BACKGROUND/AIMS: In a hypoxic state, a glycolytic system is operating as a salvage pathway of generating ATP, and hexokinase II, the first enzyme in this system, might be over-expressed in hepatocellular carcinomas (HCCs). This study was to evaluate if hexokinase II is participating in HCC cell survival in a hypoxic state, and to analyze the mechanism of cell death caused by hexokinase II-specific inhibition. METHODS: Human hepatoma cell lines were grown either in a normoxic or hypoxic condition. Hexokinase II and hypoxia-inducible factor-1alpha (HIF-1alpha) expression were evaluated using immunoblot techniques. Cell growth was assessed using the MTS assay. Apoptotic signaling cascades were explored by immunoblot analysis. RESULTS: Hypoxia stimulated HCC cellular growth through HIF-1alpha-dependent induction of hexokinase II expression. The hexokinase II-specific inhibitor, 3-bromopyruvate, significantly suppressed cellular growth in a hypoxic state compared to cells in a normoxic condition. This suppression was due to the induction of apoptosis through activating mitochondrial apoptotic signaling cascades. CONCLUSIONS: This study demonstrates that hypoxia stimulates HCC cellular growth through hexokinase II induction, and its inhibition induces apoptotic cell death. Therefore, hexokinase II induction may participate in HCC progression and the blockage of this enzyme may therapeutically be efficacious in human HCCs.
BACKGROUND/AIMS: In a hypoxic state, a glycolytic system is operating as a salvage pathway of generating ATP, and hexokinase II, the first enzyme in this system, might be over-expressed in hepatocellular carcinomas (HCCs). This study was to evaluate if hexokinase II is participating in HCC cell survival in a hypoxic state, and to analyze the mechanism of cell death caused by hexokinase II-specific inhibition. METHODS:Humanhepatoma cell lines were grown either in a normoxic or hypoxic condition. Hexokinase II and hypoxia-inducible factor-1alpha (HIF-1alpha) expression were evaluated using immunoblot techniques. Cell growth was assessed using the MTS assay. Apoptotic signaling cascades were explored by immunoblot analysis. RESULTS:Hypoxia stimulated HCC cellular growth through HIF-1alpha-dependent induction of hexokinase II expression. The hexokinase II-specific inhibitor, 3-bromopyruvate, significantly suppressed cellular growth in a hypoxic state compared to cells in a normoxic condition. This suppression was due to the induction of apoptosis through activating mitochondrial apoptotic signaling cascades. CONCLUSIONS: This study demonstrates that hypoxia stimulates HCC cellular growth through hexokinase II induction, and its inhibition induces apoptotic cell death. Therefore, hexokinase II induction may participate in HCC progression and the blockage of this enzyme may therapeutically be efficacious in human HCCs.
Authors: R A Pazo-Cid; M Lanzuela; G Esquerdo; J L Pérez-Gracia; A Antón; G Amigo; J Martínez Trufero; A L García-Otín; P Martín-Duque Journal: Clin Transl Oncol Date: 2012-07-18 Impact factor: 3.405
Authors: Eun Sun Jang; Jung-Hwan Yoon; Sung-Hee Lee; Soo-Mi Lee; Jeong-Hoon Lee; Su Jong Yu; Yoon Jun Kim; Hyo-Suk Lee; Chung Yong Kim Journal: J Cancer Res Clin Oncol Date: 2013-11-27 Impact factor: 4.553
Authors: Thomas Amann; Ulrike Maegdefrau; Arndt Hartmann; Abbas Agaimy; Jörg Marienhagen; Thomas S Weiss; Oliver Stoeltzing; Christina Warnecke; Jürgen Schölmerich; Peter J Oefner; Marina Kreutz; Anja K Bosserhoff; Claus Hellerbrand Journal: Am J Pathol Date: 2009-03-12 Impact factor: 4.307
Authors: Hwan Jun Jae; Jin Wook Chung; Hee Sun Park; Min Jong Lee; Ki Chang Lee; Hyo-Cheol Kim; Jung Hwan Yoon; Hesson Chung; Jae Hyung Park Journal: Korean J Radiol Date: 2009 Nov-Dec Impact factor: 3.500