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 (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.

[1]  D. Choi,et al.  Mediation of neuronal apoptosis by enhancement of outward potassium current. , 1997, Science.

[2]  D. Altieri,et al.  Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis. , 2004, The Journal of clinical investigation.

[3]  D. Theriaque,et al.  Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children , 2006, Pediatrics.

[4]  A. Harris,et al.  Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non small cell lung cancer and tumor-associated stroma. , 2005, Neoplasia.

[5]  M. Yaffe,et al.  Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A. , 1999, Science.

[6]  Chi V Dang,et al.  Multifaceted roles of glycolytic enzymes. , 2005, Trends in biochemical sciences.

[7]  A. Alavi,et al.  Akt Stimulates Aerobic Glycolysis in Cancer Cells , 2004, Cancer Research.

[8]  K. M. Popov,et al.  Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. , 1998, The Biochemical journal.

[9]  L. Reed.  Pyruvate Dehydrogenase Complex , 1969 .

[10]  W. Pu,et al.  NFAT Transcription Factors Are Critical Survival Factors That Inhibit Cardiomyocyte Apoptosis During Phenylephrine Stimulation In Vitro , 2003, Circulation research.

[11]  S. Archer,et al.  Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. , 2005, The Journal of clinical investigation.

[12]  P. Stacpoole.  The pharmacology of dichloroacetate. , 1989, Metabolism: clinical and experimental.

[13]  L. B. Chen,et al.  Mitochondrial membrane potential in living cells. , 1988, Annual review of cell biology.

[14]  Ulrich Brandt,et al.  Energy converting NADH:quinone oxidoreductase (complex I). , 2006, Annual review of biochemistry.

[15]  C. Murry,et al.  NFATc3-Induced Reductions in Voltage-Gated K+ Currents After Myocardial Infarction , 2004, Circulation research.

[16]  A. Hutson,et al.  Efficacy of Dichloroacetate as a Lactate‐Lowering Drug , 2003, Journal of clinical pharmacology.

[17]  Peter J Bungay,et al.  Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands. , 2006, Biochemistry.

[18]  H. Hofer,et al.  Superoxide targets calcineurin signaling in vascular endothelium. , 2005, Biochemical and biophysical research communications.

[19]  A. Murphy,et al.  Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation-reduction state. , 2002, The Biochemical journal.

[20]  F. Macian,et al.  NFAT proteins: key regulators of T-cell development and function , 2005, Nature Reviews Immunology.

[21]  S. Archer,et al.  Diversity in Mitochondrial Function Explains Differences in Vascular Oxygen Sensing , 2002, Circulation research.

[22]  L. Witters,et al.  Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart. , 1993, The Journal of biological chemistry.

[23]  Baofeng Yang,et al.  HERG K+ channel, a regulator of tumor cell apoptosis and proliferation. , 2002, Cancer research.

[24]  M. V. Heiden,et al.  Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. , 1999, Molecular cell.

[25]  B. Robinson,et al.  Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase. , 1996, The Journal of clinical investigation.

[26]  P. Stacpoole,et al.  Dichloroacetate in the treatment of lactic acidosis. , 1988, Annals of internal medicine.

[27]  D. Bers,et al.  Increased work in cardiac trabeculae causes decreased mitochondrial NADH fluorescence followed by slow recovery. , 1996, Biophysical journal.

[28]  R. Gottlieb,et al.  The mitochondrial voltage-dependent anion channel (VDAC) as a therapeutic target for initiating cell death. , 2003, Current medicinal chemistry.

[29]  C. Moraes,et al.  Titrating the Effects of Mitochondrial Complex I Impairment in the Cell Physiology* , 1999, The Journal of Biological Chemistry.

[30]  T. Haller,et al.  Activation of L-type Ca2+ channels after purinoceptor stimulation by ATP in an alveolar epithelial cell (L2). , 1995, The American journal of physiology.

[31]  R S Balaban,et al.  Nicotinamide adenine dinucleotide fluorescence spectroscopy and imaging of isolated cardiac myocytes. , 1989, Biophysical journal.

[32]  J. Hoek,et al.  Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. , 2005, Cancer research.

[33]  J. Yuan,et al.  Activation of K+ channels: an essential pathway in programmed cell death. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[34]  R. Henriksson,et al.  Induction of apoptosis by intracellular potassium ion depletion: using the fluorescent dye PBFI in a 96-well plate method in cultured lung cancer cells. , 2006, Toxicology in vitro : an international journal published in association with BIBRA.

[35]  M. Rice,et al.  Partial Mitochondrial Inhibition Causes Striatal Dopamine Release Suppression and Medium Spiny Neuron Depolarization via H2O2 Elevation, Not ATP Depletion , 2005, The Journal of Neuroscience.

[36]  C. Thompson,et al.  Cell metabolism in the regulation of programmed cell death , 2002, Trends in Endocrinology & Metabolism.

[37]  P. Daleau,et al.  Hydrogen peroxide modulates the Kv1.5 channel expressed in a mammalian cell line , 2003, Naunyn-Schmiedeberg's Archives of Pharmacology.

[38]  J. Dyck,et al.  Dichloroacetate Prevents and Reverses Pulmonary Hypertension by Inducing Pulmonary Artery Smooth Muscle Cell Apoptosis , 2004, Circulation research.

[39]  L. Augenlicht,et al.  The intrinsic mitochondrial membrane potential of colonic carcinoma cells is linked to the probability of tumor progression. , 2005, Cancer research.

[40]  Zhiguo Wang.  Roles of K+ channels in regulating tumour cell proliferation and apoptosis , 2004, Pflügers Archiv.

[41]  S. Archer,et al.  Hypoxic pulmonary vasoconstriction: redox regulation of O2-sensitive K+ channels by a mitochondrial O2-sensor in resistance artery smooth muscle cells. , 2004, Journal of molecular and cellular cardiology.

[42]  G. Kroemer,et al.  The mitochondrion in apoptosis: how Pandora's box opens , 2001, Nature Reviews Molecular Cell Biology.

[43]  R. Clayton,et al.  Cytochrome c release from rat brain mitochondria is proportional to the mitochondrial functional deficit: implications for apoptosis and neurodegenerative disease , 2005, Journal of neurochemistry.

[44]  R. Gillies,et al.  Why do cancers have high aerobic glycolysis? , 2004, Nature Reviews Cancer.

[45]  J. Trimmer,et al.  Membrane Depolarization Inhibits Kv1.5 Voltage-gated K Channel Gene Transcription and Protein Expression in Pituitary Cells (*) , 1995, The Journal of Biological Chemistry.

[46]  Masashi Narita,et al.  Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC , 1999, Nature.

[47]  S. Wölfl,et al.  Expression of voltage-gated potassium channels Kv1.3 and Kv1.5 in human gliomas , 2003, Neuroscience Letters.

[48]  J. Dyck,et al.  In Vivo Gene Transfer of the O2-Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats , 2003, Circulation.

[49]  Svetlana V Komarova,et al.  Convergent signaling by acidosis and receptor activator of NF-kappaB ligand (RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[50]  P. Hogg,et al.  Mitochondria as cancer drug targets. , 2004, Trends in molecular medicine.

[51]  E. Schon,et al.  Neuronal degeneration and mitochondrial dysfunction. , 2003, The Journal of clinical investigation.