PCK2 opposes mitochondrial respiration and maintains the redox balance in starved lung cancer cells

Cancer cells frequently lack nutrients like glucose, due to insufficient vascular networks. A decrease of extracellular glucose is accompanied by enhanced mitochondrial respiration in cancer cells, which promotes the formation of potentially harmful reactive oxygen species (ROS). Here we show that a gluconeogenesis enzyme, mitochondrial phosphoenolpyruvate carboxykinase, PCK2, acts as a regulator of mitochondrial respiration and maintains the redox balance in nutrient-deprived lung cancer cells. PCK2 silencing increased the abundance and interconversion of tricarboxylic acid (TCA) cycle intermediates, augmented mitochondrial respiration and enhanced glutathione oxidation under glucose and serum starvation, in a PCK2 re-expression reversible manner. Moreover, augmenting the TCA cycle by PCK2 inhibition severely reduced colony formation. As a conclusion, PCK2 contributes to maintaining a reduced glutathione pool upon starvation besides mediating the biosynthesis of gluconeogenic/glycolytic intermediates. The study sheds light on adaptive responses in cancer cells to nutrient deprivation and identifies gluconeogenesis as starvation-induced pathway that limits respiration-induced oxidative stress.