High tumor heterogeneity and increased therapy resistance acquired in a hypoxic tumor microenvironment remain major obstacles to successful radiotherapy. Others and we have shown that adaptation of cancer cells to cycling severe hypoxia and intermittent reoxygenation stress (chronic-cycling hypoxia) increases cellular antioxidant capacity thereby supporting resistance to chemotherapy and radiotherapy. Here we explored the involvement of antioxidant-associated mitochondrial transport-systems for maintenance of redox-homeostasis in adaptation to chronic-cycling hypoxia and associated radioresistance.

Genetic or pharmacological inhibition of the mitochondrial dicarboxylate carrier (SLC25A10) or the oxoglutarate-carrier (SLC25A11) increased the cytotoxic effects of ionizing radiation (IR). But only targeting of SLC25A10 was effective in overcoming chronic-cycling hypoxia-induced enhanced death resistance in vitro and in vivo by disturbing increased antioxidant capacity. Furthermore, in silico analysis revealed that overexpression of SLC25A10 but not SLC25A11 is associated with reduced overall survival in lung- and breast-cancer patients.

Our study reveals a role of SLC25A10 in supporting both, redox- and energy-homeostasis, ensuring radioresistance of cancer cells with tolerance to chronic-cycling hypoxia thereby proposing a novel strategy to overcome a mechanism of hypoxia-induced therapy resistance with potential clinical relevance regarding decreased patient survival.