Anales RANF

S12-02 EXTRA- AND INTRACELLULAR METABOLISM OF ADENOSINE IN CANCER AND INFLAMMATION K. Losenkova, S.Jalkanen, G.G. Yegutkin University of Turku, Turku, Finland Current models of cellular purine turnover depend of functional interactions between distinct processes, including (i) the release of endogenous ATP, (ii) triggering of signaling events via nucleotide- and nucleoside-selective receptors, (iii) ectoenzymatic interconversion of extracellular nucleotides, (iv) cellular uptake of nucleotide-derived adenosine and other nucleosides via equilibrative nucleoside transporters and finally, (v) intracellular interconversion of the transported nucleosides into ATP through complex phosphotransfer reactions. Despite the significant progress in our understanding of the purinergic machinery as a multistep cascade, current knowledge on the whole sequence of “release-signaling-inactivation” remains rather limited. The adenosine pathway is currently viewed as a significant barrier to the effectiveness of immune therapies and becomes an important therapeutic target in cancer. Prior research has focused almost exclusively on adenosine producing ectoenzymes, nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39) and ecto-5’-nucleotidase/CD73, and on the role of different types of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) with mixed findings of anti-tumor and pro-tumor effects of the different receptors. Major gaps in knowledge that impede the development of effective adenosine-based therapeutics include: (1) lack of consideration of redundant pathways controlling adenosine levels, and (2) lack of distinction between receptor-mediated and epigenetic receptor- independent effects of adenosine. In particular, along with “classical” CD39-CD73 axis, other membrane-bound and secreted enzymes contribute to the tuned control of extracellular adenosine levels, including the enzymes of the nucleotide pyrophosphatase/phosphodiesterase, alkaline phosphatase, adenylate kinase and nucleoside diphosphate kinase (NDPK/NME/NM23) families, CD38, adenosine deaminase and purine nucleoside phosphorylase. Here, we summarize recent advances in this rapidly evolving field, with particular emphasis on adenosine-producing and – inactivating pathways at such (patho)physiological states as inflammation, hypoxia and tumorigenesis.