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.
Highlights
Disorganization of tumor vascular networks that generates inter-capillary distances beyond oxygen diffusion range (100–200 μm) leads to hypoxia as a common feature in cancers [1]
Mitochondria increase the levels of cytosolic reactive oxygen species (ROS) during hypoxia, where ROS is produced at the Qo site of the mitochondrial complex III [41]
We find that ROS promotes tumor-repopulating cells (TRCs) growth by activating NF-κB and Akt pathways, and inhibiting either NF-κB or Akt blocks the effect of ROS on TRC growth
Summary
We aimed to validate the above in vivo results in vitro
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