Cancer Cell

A Metabolic-Electrical Remodeling in Cancer

Figure 1. A Reversible Metabolic-Electrical Remodeling in Cancer Contributes to Resistance to Apoptosis and Reveals Several

Potential Therapeutic Targets

In cancer, mitochondrial glucose oxidation is inhibited and energy production relies on the cytoplasmic glycolysis. This ‘‘inactivity’’ of the mito- chondria likely induces a state of apoptosis resistance. Activation of PDH by DCA increases glucose oxidation by promoting the influx of acetyl- CoA into the mitochondria and the Krebs cycle, thus increasing NADH delivery to complex I of the electron transport chain, increasing the production of superoxide, which in the presence of MnSOD is dismutated to the more stable H2O2. Sustained increase in ROS generation can damage the redox-

sensitive complex I, inhibiting H+ efflux and decreasing DJm. Opening of the DJm-sensitive mitochondrial transition pore (MTP) allows the efflux of

cytochrome c and apoptosis inducing factor (AIF). Both cytochrome c and H2O2 open the redox-sensitive K+ channel Kv1.5 in the plasma membrane and hyperpolarize the cell (increased Em), inhibiting a voltage-dependent Ca2+ entry. The decreased [Ca2+]i suppresses a tonic activation of NFAT, resulting in its removal from the nucleus, thus increasing Kv1.5 expression. The increased efflux of K+ from the cell decreases the tonic inhibition of [K+]i on caspases, further enhancing apoptosis. DCA’s selectivity is based on its ability to target the unique metabolic profile that characterizes most cancers, and its effectiveness is explained by its dual mechanism of apoptosis induction, both by depolarizing mitochondria (proximal pathway) and activating/upregulating Kv1.5 (distal pathway).