title: A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth.
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.
authors.affiliation: Pulmonary Hypertension Program and Vascular Biology Group, Department of Physiology, University of Alberta, Edmonton, AB T6G 2B7, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
authors.forename: Joan
authors.initials: J
authors.lastname: Allalunis-Turner
authors.forename: Alois
authors.initials: A
authors.lastname: Haromy
authors.forename: Christian
authors.initials: C
authors.lastname: Beaulieu
authors.forename: Richard
authors.initials: R
authors.lastname: Thompson
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Lee
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Puttagunta
authors.forename: Sandra
authors.initials: S
authors.lastname: Bonnet
authors.forename: Gwyneth
authors.initials: G
authors.lastname: Harry
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Porter
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Andrade
authors.forename: Bernard
authors.initials: B
authors.lastname: Thebaud
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D003999:Dichloroacetic Acid / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D011923:Rats, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D050778:NFATC Transcription Factors; C000631430:PDK2 protein, human; C000631436:Pdk2 protein, rat; D015221:Potassium Channels; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D003999:Dichloroacetic Acid; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases