Ascorbate and the Hypoxic Response in Cancer
Low oxygen (hypoxia) is a characteristic of most solid tumors, leading to resistance to therapy and poor prognosis for cancer patients. Specific transcription factors, hypoxia-inducible factors (HIFs), respond to these adverse conditions by upregulating a myriad of responsive genes that increase cell survival, proliferation, angiogenesis, and tumor spread. HIF transcription factors are regulated predominantly at the posttranslational level via protein stabilization and activation under hypoxia. Under normoxic conditions, HIF proteins are degraded and inactivated. These modifications on HIF are carried out by hydroxylase enzymes belonging to the family of 2-oxoglutarate-dependent dioxygenases. Besides oxygen, Fe2+, and 2-oxoglutarate, the HIF hydroxylases require ascorbate for activity. This chapter describes what we know regarding the importance of ascorbate for the regulation of the HIF pathway in cancer.