Abstract
The central issue of resistance to radiation remains a significant challenge in the treatment of cancer despite improvements in treatment modality and emergence of new therapies. To facilitate the identification of molecular factors that elicit protection against radiation, we developed a matched model of radiation resistance for head and neck cancer (HNC) and characterized its properties using selective chemical probes for protein oxidation, omics technologies and complementary assays. Functional network analysis of proteomics data identified DNA replication and base excision repair, ECM‐receptor interaction, and regulation of actin cytoskeleton as significantly up‐ or down‐regulated networks in resistant (rSCC‐61) HNC cells. Up‐regulated proteins in rSCC‐61 included enzymes involved in lipid metabolism and antioxidant system. Redox proteomics analysis using biotin‐tagged chemical probes and mass spectrometry identified decreased oxidative damage of the antioxidant system in rSCC‐61 consistent with the cells increased ability to withstand a radiation insult. Further metabolomics and epigenetics studies of this system show that multiple pathways converge to produce the rSCC‐61 phenotype and point to the function of the antioxidant system as major regulator of resistance to ionizing radiation in rSCC‐61, a phenomenon confirmed by analysis of HNC tumor samples.
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