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Review
. 2022 Jul;43(7):1623-1632.
doi: 10.1038/s41401-021-00800-7. Epub 2021 Nov 22.

The double faced role of xanthine oxidoreductase in cancer

Man-Man Chen  1   2 , Ling-Hua Meng  3   4
Affiliations
Review

The double faced role of xanthine oxidoreductase in cancer

Man-Man Chen et al. Acta Pharmacol Sin. 2022 Jul.

Abstract

Xanthine oxidoreductase (XOR) is a critical, rate-limiting enzyme that controls the last two steps of purine catabolism by converting hypoxanthine to xanthine and xanthine to uric acid. It also produces reactive oxygen species (ROS) during the catalytic process. The enzyme is generally recognized as a drug target for the therapy of gout and hyperuricemia. The catalytic products uric acid and ROS act as antioxidants or oxidants, respectively, and are involved in pro/anti-inflammatory actions, which are associated with various disease manifestations, including metabolic syndrome, ischemia reperfusion injury, cardiovascular disorders, and cancer. Recently, extensive efforts have been devoted to understanding the paradoxical roles of XOR in tumor promotion. Here, we summarize the expression of XOR in different types of cancer and decipher the dual roles of XOR in cancer by its enzymatic or nonenzymatic activity to provide an updated understanding of the mechanistic function of XOR in cancer. We also discuss the potential to modulate XOR in cancer therapy.

Keywords: ROS; cancer therapy; uric acid; xanthine oxidoreductase (XOR).

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Catabolism of purine nucleosides.
Xanthine oxidoreductase (XOR) is the rate-limiting enzyme that controls the last two steps of purine catabolism by converting hypoxanthine to xanthine and xanthine to uric acid. Inhibitors of XOR such as allopurinol, febuxostat, and topiroxostat are able to inhibit the process. IMPDH inosine monophosphate dehydrogenase, ADSL adenylosuccinate lyase, ADSS adenylosuccinate synthase, GMPS guanine monophosphate, cN-I cytosolic 5ʹ-nucleotidase I, cN-II cytosolic 5’-nucleotidase II, ADA adenosine deaminase, GDA guanine deaminase, PNP purine nucleoside phosphorylase.
Fig. 2
Fig. 2. The structure and physiological function of XOR.
XOR is a homodimer and each subunit composes of two non-identical iron-sulfur clusters (2Fe/S), a flavin adenine dinucleotide (FAD) cofactor, and a molybdopterin cofactor (Mo-co) domain. XOR acts as xanthine dehydrogenase (XDH), xanthine oxidase (XO), nicotinamide adenine dinucleotide (NADH) oxidase, and nitrate reductase under different circumstances, participating in purine metabolism, detoxification, and redox homeostasis.
Fig. 3
Fig. 3. Differential expression of XOR in normal and tumor tissues.
The expression of XOR at mRNA level was recruited from TCGA database and plotted using the TIMER (https://cistrome.shinyapps.io/timer/). *P < 0.05; **P < 0.01; ***P < 0.001.
Fig. 4
Fig. 4. The double faced role of XOR in cancer.
XOR may exert protumoral or tumor suppressive role via modulating tumor cells as well tumor microenviroment by its catalytic products uric acid and ROS.
See this image and copyright information in PMC

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