Hexokinase II detachment from the mitochondria potentiates cisplatin induced cytotoxicity through a caspase-2 dependent mechanism

Cell Cycle. 2009 Oct 15;8(20):3355-64. doi: 10.4161/cc.8.20.9853. Epub 2009 Oct 19.

Abstract

Cancer cells are frequently glycolytic and overexpress hexokinase II (HXK II). In cancer cells, the majority of hexokinase II is localized to the mitochondria through interaction with the voltage dependent anion channel (VDAC). Disruption in the binding of hexokinase II to the mitochondria has been shown to promote mitochondrial injury provoked by pro-apoptotic proteins. The present study demonstrates that cisplatin induces the PIDD (p53 induced protein with a death domain) dependent activation of caspase-2. In turn, caspase-2 cleaves and activates Bid, resulting in the oligomerization of Bak and the release of cytochrome c. Notably, the detachment of hexokinase II from the mitochondria markedly potentiates the onset of caspase-2 induced mitochondrial damage, thus resulting in a synergistic induction of cisplatin induced cytotoxicity.

MeSH terms

  • Antineoplastic Agents / toxicity*
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Carrier Proteins / metabolism
  • Caspase 2 / metabolism*
  • Cell Line, Tumor
  • Cisplatin / toxicity*
  • Cytochromes c / metabolism
  • Death Domain Receptor Signaling Adaptor Proteins
  • Hexokinase / analysis
  • Hexokinase / metabolism*
  • Humans
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Voltage-Dependent Anion Channels / metabolism
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism

Substances

  • Antineoplastic Agents
  • BH3 Interacting Domain Death Agonist Protein
  • Carrier Proteins
  • Death Domain Receptor Signaling Adaptor Proteins
  • PIDD1 protein, human
  • Voltage-Dependent Anion Channels
  • bcl-2 Homologous Antagonist-Killer Protein
  • Cytochromes c
  • Hexokinase
  • Caspase 2
  • Cisplatin