A Low-dose Arsenic-induced p53 Protein-mediated Metabolic Mechanism of Radiotherapy Protection

Background: Radiotherapy protection depends on a selective protection of normal tissues but not tumors. Results: We demonstrate that low doses of arsenic induce a p53/HIF-1-dependent metabolic reprogramming specific to normal cells, resulting in increased resistance to radiation toxicity. Conclusion: p53-mediated metabolic reprogramming can be explored for normal tissue protection. Significance: The use of low-dose arsenic for selective protection of normal tissues may have important therapeutic implications.Radiotherapy is the current frontline cancer treatment, but the resulting severe side effects often pose a significant threat to cancer patients, raising a pressing need for the development of effective strategies for radiotherapy protection. We exploited the distinct metabolic characteristics between normal and malignant cells for a metabolic mechanism of normal tissue protection. We showed that low doses of arsenic induce HIF-1, which activates a metabolic shift from oxidative phosphorylation to glycolysis, resulting in increased cellular resistance to radiation. Of importance is that low-dose arsenic-induced HIF-1 requires functional p53, limiting the glycolytic shift to normal cells. Using tumor-bearing mice, we provide proof of principle for selective normal tissue protection against radiation injury.