Figure 1.
(A) Structure and function of CD73/NT5E. The membrane bound ecto-5′-nucleotidase NT5E hydrolyzes extracellular adenosine monophosphate (AMP) into adenosine and inorganic phosphate (P). Upstream of NT5E, adenosine triphosphate (ATP) is hydrolyzed via two reaction steps into AMP by the enzyme ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1) (CD39). Adenosine thus produced exerts anti-inflammatory effects by binding to the adenosine A2A receptor (ADORA2A) expressed by T cells, natural killer (NK) cells, and dendritic cells (DCs) resulting in cAMP mediated blocking of their effector functions. To some extent, the A2B receptor (ADORA2B) is also expressed on DCs and macrophages which are suppressed by adenosine. Thus, cancer cells can evade the immune system by upregulating NT5E protein levels. Furthermore, adenosine binds to the A2B receptor expressed by cancer cells leading to tumor cell survival and proliferation. Cancer cells also express the adenosine A1 receptor (ADORA1) and A3 receptor (ADORA3) and binding of adenosine to these receptors leads to tumor cell migration and proliferation via signaling through Gαi proteins. Adenosine is also involved in the adaption to hypoxia and shows pro-angiogenic potential. All adenosine receptors are depicted as stylized green transmembrane proteins. Adenosine is also symbolized as yellow circles marked with “A”. (B) Network of transcription factors and microRNAs (miRNAs) regulating NT5E expression. This network summarizes the current knowledge on regulation of NT5E on transcriptional (TFs) and posttranscriptional level by TFs and miRNAs, respectively. Transcriptional activators are depicted in blue and transcriptional repressors are highlighted in magenta. miRNAs targeting NT5E directly are shown, as well as miRNAs with indirect impact on NT5E expression through targeting of transcriptional regulators.