Transcription profiling of lung carcinoma and brain glioblastoma cells were analalyzed, with microarrays run both for control and treatment with dichloroacetate reveals a mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis inhibits cancer growth

The unique metabolic profile of most cancers (aerobic glycolysis) might confer apoptosis-resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential and low expression of the K+ channel Kv1.5, both contributing to apoptosis-resistance. Dichloroacetate (DCA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases mitochondrial membrane potential, 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 tumor growth in vitro and in vivo, 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 novel selective anticancer agent. Experiment Overall Design: lung carcinoma and brain glioblastoma cells were analalyzed, with microarrays run both for control and treatment with DCA