A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth

Cancer Cell. 2007 Jan;11(1):37-51. doi: 10.1016/j.ccr.2006.10.020.

Abstract

The unique metabolic profile of cancer (aerobic glycolysis) might confer apoptosis resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential (DeltaPsim) and low expression of the K+ channel Kv1.5, both contributing to apoptosis resistance. Dichloroacetate (DCA) inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases DeltaPsim, increases mitochondrial H2O2, and activates Kv channels in all cancer, but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation, and inhibits tumor growth, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a promising selective anticancer agent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Cell Line, Tumor
  • Dichloroacetic Acid / pharmacology
  • Humans
  • Immunoblotting
  • Membrane Potential, Mitochondrial / drug effects
  • Membrane Potential, Mitochondrial / physiology
  • Microscopy, Confocal
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • NFATC Transcription Factors / metabolism
  • Neoplasms / metabolism*
  • Patch-Clamp Techniques
  • Potassium Channels / drug effects
  • Potassium Channels / metabolism*
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Rats
  • Rats, Nude
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • NFATC Transcription Factors
  • PDK2 protein, human
  • Pdk2 protein, rat
  • Potassium Channels
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Dichloroacetic Acid
  • Protein Kinases
  • Protein-Serine-Threonine Kinases