The interplay between the thioredoxin system and hypoxia-related factors in cancer

Hypoxia constitutes a common feature of tumor microenvironments, orchestrating cancer progression across various malignancies. Cancer growth and resistance to therapy are frequently associated with overexpression of antioxidant systems, such as the thioredoxin (Trx) system. This system is fundamental for cell survival and proliferation, playing a key role in maintaining redox homeostasis and regulating hypoxia-inducible factor-1alpha (HIF-1α) activity. This, in turn, regulates different genes involved in tumor progression, such as the vascular endothelial growth factor (VEGF), an indispensable factor for tumor invasiveness and microenvironment tumor maintenance. HIF-1α can also be regulated by the signal transducer and activator of transcription 3 (STAT3), an oncogene stimulated by pro-inflammatory cytokines and growth factors. Targeting antioxidant systems, such as the Trx system, is an emerging strategy in cancer therapy, as tumor cells are more vulnerable to disruptions in redox homeostasis than normal cells. Even though there are some studies correlating the use of Trx inhibitors and the inhibition of hypoxia-related factors, the diverse pathways in which this occurs are still elusive. Therefore, in this review, we explore the multiple pathways through which the Trx system influences HIF-1α and highlight drugs that have been studied targeting hypoxia-related factors by inhibiting the Trx system. Given the link between oxidative stress and apoptosis in cancer cells, and the low overall survival rates for many cancers despite new therapies, understanding the Trx system's connection to hypoxia-related pathways could be crucial for advancing therapeutic approaches and tackling therapy resistance.