A Mitochondria-K + Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth

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 (ΔΨm) and low expression of the K + channel Kv1.5, both contributing to apoptosis...

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Bibliographic Details
Published in:Cancer cell 2007, Vol.11 (1), p.37-51
Main Authors: Bonnet, Sébastien, Archer, Stephen L., Allalunis-Turner, Joan, Haromy, Alois, Beaulieu, Christian, Thompson, Richard, Lee, Christopher T., Lopaschuk, Gary D., Puttagunta, Lakshmi, Bonnet, Sandra, Harry, Gwyneth, Hashimoto, Kyoko, Porter, Christopher J., Andrade, Miguel A., Thebaud, Bernard, Michelakis, Evangelos D.
Format: Article
Language:English
Subjects:
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
Neoplasms - metabolism
NFATC Transcription Factors - metabolism
Patch-Clamp Techniques
Potassium Channels - drug effects
Potassium Channels - metabolism
Protein Kinases - metabolism
Protein-Serine-Threonine Kinases
Rats
Rats, Nude
Reverse Transcriptase Polymerase Chain Reaction
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Summary: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 (ΔΨm) 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 ΔΨm, increases mitochondrial H 2O 2, 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.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2006.10.020