Inhibition of the Thioredoxin System: Regulation by the Cancer Cell Environment

Abstract

The oxygen environment in tumors is not static and involves constant cycling between hypoxic and re-oxygenation phases, a phenomenon known as intermittent hypoxia. Hypoxic and redox pathways are upregulated in response to intermittent hypoxia. The thioredoxin system, comprised of thioredoxin and thioredoxin reductase, is one of the main antioxidant systems, while hypoxia inducible factor 1 (HIF1) is the major hypoxia responsive system. High levels of both the thioredoxin system proteins and HIF1α have been correlated with extremely aggressive and highly metastatic tumors. Both these systems have also been linked to development of resistance against anti-cancer therapies. Moreover, HIF1α is indirectly redox regulated by thioredoxin, suggesting a potential cross-talk between the two systems, which becomes more apparent under intermittent hypoxia. Therefore, an understanding of these two systems under different oxygen conditions occurring in cancers may aid in the designing more effective therapeutics.