Xanthine oxidoreductase in cancer: more than a differentiation marker

Abstract

Human xanthine oxidoreductase (XOR) catalyzes the last two steps of purine catabolism and is present in two interconvertible forms, which may utilize O2 or NAD + as electron acceptors. In addition to uric acid, XOR products may comprise reactive oxygen and nitrogen species that have many biologic effects, including inflammation, endothelial dysfunction, and cytotoxicity, as well as mutagenesis and induction of proliferation. XOR is strictly modulated at the transcriptional and post‐translational levels, and its expression and activity are highly variable in cancer. Xanthine oxidoreductase (XOR) expression has been negatively associated with a high malignity grade and a worse prognosis in neoplasms of the breast, liver, gastrointestinal tract, and kidney, which normally express a high level of XOR protein. However, the level of XOR expression may be associated with a worse outcome in cancer of low XOR‐expressing cells, in relation to the inflammatory response elicited through the tissue damage induced by tumor growth. Xanthine oxidoreductase (XOR) has been implicated in the process of oncogenesis either directly because it is able to catalyze the metabolic activation of carcinogenic substances or indirectly through the action of XOR‐derived reactive oxygen and nitrogen species. The role of uric acid is characterized by both oxidant and antioxidant action; thus, it is still debatable whether control of uricemia may be helpful to improve the outcomes of tumor illness.

Loss of Xanthine Oxidoreductase Potentiates Propagation of Hepatocellular Carcinoma Stem Cells

“…XOR, a housekeeping enzyme, is known as the rate‐limiting enzyme in purine catabolism, and is predominantly expressed in the liver . Multiple lines of evidence have determined that XOR functions as a multifunctional enzyme and is involved in various physiological and pathological responses, including cancer . Fiorenzo et al first reported that the expression of XOR was significantly elevated in livers with virus‐related cirrhosis and that low XOR activity was detected in HCC tissue compared with the adjacent peritumor .…”

Repeated measurements of serum urate and mortality: a prospective cohort study of 152,358 individuals over 8 years of follow-up

“…An annual decrease or increase in serum urate was associated with a 2.3-and 1.6-fold increased risk of cancer mortality, respectively. Prior studies on serum urate with cancer mortality have yielded conflicting results [14,29,44,[50][51][52][53][54], with some reporting lower risk [51,52]and some reporting increased risk [14,29,44,53,54] of cancer mortality. Potential explanations for these inconsistent findings include not being able to examine both low and high serum urate levels, incomplete covariate adjustment, and inability to examine changes in serum urate with cancer mortality.…”

Inhibition of Xanthine Oxidoreductase Enhances the Potential of Tyrosine Kinase Inhibitors against Chronic Myeloid Leukemia

“…The downregulation and upregulation of XOR activity have been related to different types of solid tumors [47], suggesting the importance of XOR produced ROS in tumorigenesis [48]. Besides, a higher XOR activity has been related with relapsed acute myeloid leukemia [49].…”