Abstract
Clinical applications of antiangiogenic agents profoundly affect tumor cell behaviors via the resultant hypoxia. To date, how the hypoxia regulates tumor cells remains unclear. Here, we show that hypoxia promotes the growth of human breast tumorigenic cells that repopulate tumors [tumor-repopulating cells (TRCs)] in vitro and in vivo. This stimulating effect is ascribed to hypoxia-induced reactive oxygen species (ROS) that activates Akt and NF-κB, dependent on the attenuated tricarboxylic acid (TCA) cycle. We find that fumarate is accumulated in the TCA cycle of hypoxic TRCs, leading to glutathione succination, NADPH/NADP+ decrease, and an increase in ROS levels. Mechanistically, hypoxia-increased HIF-1α transcriptionally downregulates the expression of mitochondrial phosphoenolpyruvate carboxykinase (PCK2), leading to TCA cycle attenuation and fumarate accumulation. These findings reveal that hypoxia-reprogrammed TCA cycle promotes human breast TRCs growth via a HIF-1α-downregulated PCK2 pathway, implying a need for a combination of an antiangiogenic therapy with an antioxidant modulator.