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

Geum Youn Gwak, Jung Hwan Yoon, Kang Mo Kim, Hyo Suk Lee, Jin Wook Chung, Gregory J. Gores

Research output: Contribution to journalArticle

137 Scopus citations

Abstract

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-1α (HIF-1α) 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-1α-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.

Original languageEnglish (US)
Pages (from-to)358-364
Number of pages7
JournalJournal of hepatology
Volume42
Issue number3
DOIs
StatePublished - Mar 2005

Keywords

  • Hepatocellular carcinoma
  • Hexokinase II
  • Hypoxia
  • Hypoxia-inducible factor-1α

ASJC Scopus subject areas

  • Hepatology

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