Mitochondrial superoxide dismutase controls metabolic plasticity in pancreatic cancer.

BACKGROUND

The role of reactive oxygen species (ROS) in cancer is debated. One main antioxidant enzyme is mitochondrial superoxide dismutase (SOD2) which has been shown to influence tumor initiation and metastatic progression in several cancer types.

METHODS

To investigate the impact of Sod2 deletion on pancreatic cancer biology and metabolism, we used CRISPR/Cas9 gene editing to generate 3 independent Sod2-deficient cell lines from murine KrasG12D pancreatic cancer cell lines and analyzed them for proliferation, colony forming, mitochondrial respiration and RNA expression. In addition, mass spectrometry and isotope tracing were performed.

RESULTS

Proliferation and wound healing capacity were significantly impaired in Sod2 deficient cell lines. Myc levels were significantly elevated in Sod2-deficient cells, and mitochondrial respiration was consecutively increased. This resulted in increased tolerance to glucose deprivation. Mechanistically, we detected a significantly reduced activity of succinate dehydrogenase (SDH) in Sod2-deficient cells. This resulted in increased peroxynitrite formation which was the cause of increased Myc activation.

CONCLUSIONS

These findings reveal that Sod2 shapes cellular metabolism in pancreatic cancer through peroxynitrite formation and Myc activation.