Ascorbate as a co-factor for fe- and 2-oxoglutarate dependent dioxygenases: physiological activity in tumor growth and progression

Abstract

Ascorbate is a specific co-factor for a large family of enzymes known as the Fe- and 2-oxoglutarate-dependent dioxygenases. These enzymes are found throughout biology and catalyze the addition of a hydroxyl group to various substrates. The proline hydroxylase that is involved in collagen maturation is well known, but in recent times many new enzymes and functions have been uncovered, including those involved in epigenetic control and hypoxia-inducible factor (HIF) regulation. These discoveries have provided crucial mechanistic insights into how ascorbate may affect tumor biology. In particular, there is growing evidence that HIF-1-dependent tumor progression may be inhibited by increasing tumor ascorbate levels. However, rigorous clinical intervention studies are lacking. This review will explore the physiological role of ascorbate as an enzyme co-factor and how this mechanism relates to cancer biology and treatment. The use of ascorbate in cancer should be informed by clinical studies based on such mechanistic hypotheses.

Keywords: TET enzymes; ascorbate; cancer; hydroxylation; hypoxia-inducible factor-1; tumor microenvironment; vitamin C.

Figure 1

2-Oxoglutarate-dependent dioxygenase reaction cycle and factors affecting their activity in mammalian cells. (A) Representation of 2-OGDD catalytic cycle. One atom of molecular oxygen is incorporated into the hydroxylated substrate and the other into succinate. 2-OG is converted to succinate, releasing CO₂. Ferrous iron and ascorbate are specific co-factors for this reaction. (B) Cellular stressors deprive 2-OGDDs of their required co-factors resulting in inhibition of multiple potential pathways.

Figure 2

Chemical structures of ascorbate and its oxidation products. At physiological pH, ascorbate exists as the ascorbate monoanion and can undergo two consecutive, reversible, one-electron oxidations to produce the ascorbate radical and dehydroascorbate, respectively. Adapted from Kall (73).

Figure 3

The effect of plasma ascorbate availability on delivery to remote tumor tissue and activity of the HIF-hydroxylases. Higher plasma ascorbate results in increased penetration of remote and hypoxic regions and the ability to down-regulate HIF-1 by promotion of the regulatory hydroxylases. HIF-1 mediated changes that regulate the tumor glycolytic phenotype, cell survival pathways, and angiogenesis could be affected, decreasing tumor viability and improving treatment outcomes. The epigenetic demethylases that also belong to the 2-OGDD family are also likely to be affected but little is known about these processes in cancer cells.