Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer

Abstract

The immunosuppressive effect of adenosine in the microenvironment of a tumor is well established. Presently, researchers are developing approaches in immune therapy that target inhibition of adenosine or its signaling such as CD39 or CD73 inhibiting antibodies or adenosine A2A receptor antagonists. However, numerous enzymatic pathways that control ATP-adenosine balance, as well as understudied intracellular adenosine regulation, can prevent successful immunotherapy. This review contains the latest data on two adenosine-lowering enzymes: adenosine kinase (ADK) and adenosine deaminase (ADA). ADK deletes adenosine by its phosphorylation into 5'-adenosine monophosphate. Recent studies have revealed an association between a long nuclear ADK isoform and an increase in global DNA methylation, which explains epigenetic receptor-independent role of adenosine. ADA regulates the level of adenosine by converting it to inosine. The changes in the activity of ADA are detected in patients with various cancer types. The article focuses on the biological significance of these enzymes and their roles in the development of cancer. Perspectives of future studies on these enzymes in therapy for cancer are discussed.

Keywords: ADA; ADK-L; ADK-S; adenosine; cancer therapy; tumor microenvironment.

Figure 1

Adenosine metabolism. The canonical pathway of adenosine synthesis involves the hydrolysis of ATP to AMP by ecto-nucleoside triphosphate diphosphohydrolase (NTPDase1, CD39) and the hydrolysis of AMP by ecto-5′-nucleotidase (5′NT, CD73). The non-canonical pathway involves the use of NAD⁺ as a substrate by CD38 or CD157 to generate ADP-ribose (ADPR) directly or through its cyclic form (cADPR). ADPR is then processed to AMP by CD203a (Ectonucleotide Pyrophosphatase/Phosphodiesterase 1). Extracellular adenosine can bind to its receptors or be metabolized to inosine by ecto-adenosine deaminase (ecto-ADA). Adenosine is transported into and out of the cell by concentrative or equilibrative nucleoside transporters (NTs). Intracellular adenosine synthesis is controlled by the balance of the activity of enzymes: adenosine kinase (ADK), cytoplasmic 5′nucleotidase (Cyto-5′NT), adenosine deaminase (ADA). Adenosine is generated as an end product in the transmethylation reaction: transmethylation reactions include the transfer of methyl groups from S-adenosylmethionine (SAM) to a wide range of acceptors. The resulting product, S-adenosylhomocysteine (SAH), is then cleaved by SAH hydrolase (SAHH) into adenosine and homocysteine.

Figure 2

The effect of adenosine on tumor-infiltrating cells. Adenosine can bind to four different G-protein-coupled adenosine receptors that either stimulate (mediated by A2A and A2B adenosine receptors) or inhibit (mediated by A1 and A3 adenosine receptors) adenylate cyclase activity and cAMP production in the cell. Activation of adenosine receptors on various types of cells in the tumor microenvironment can lead to the formation of immunosuppressive conditions and inhibition of the anti-tumor immune response. Abbreviations: ATP: adenosine triphosphate; cAMP: cyclic adenosine monophosphate; Treg: regulatory T cells; Foxp3: forkhead box P3; APCs: antigen-presenting cells; MDSCs: myeloid-derived suppressor cells; VEGF: vascular endothelial growth factor; bFGF: basic fibroblast growth factor.

Figure 3

Targeting adenosine in cancer therapy. Possible adenosine-associated targets for cancer therapy. Signaling, and extracellular and intracellular metabolism may be involved in limiting the immunosuppressive action of adenosine. Possible therapeutic targets are A2A receptors (A2AR) on T cells, and A2B and A3 receptors on tumor cells. Like a part of the extracellular metabolism, the CD39-CD73 axis and the CD38/CD157-CD203a-CD73 axis are actively investigated in clinical trials. Targeting adenosine-cleaving enzymes, ADK and ADA, as well as nucleotide transporters, may become a new direction in cancer therapy. Of particular interest is ADK-L, which is involved in epigenetic regulation.