Hypoxia stimulates proliferation of human hepatoma cells through the induction of hexokinase II expression

Background/Aims: In a hypoxic state, a glycolytic system is operating as a salvage pathway of generating ATP, and hexokinase 11, the first enzyme in this system, might be over-expressed in hepatocellular carcinomas (HCCs). This study was to evaluate if hexokinase 11 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-1 alpha (HIF-1 alpha) expression were evaluated using immunoblot techniques. Cell growth was assessed using the NITS assay. Apoptotic signaling cascades were explored by immunoblot analysis. Results: Hypoxia stimulated HCC cellular growth through HIF-1 alpha-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. (c) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.