title: Adenosine inhibits tumor cell invasion via receptor-independent mechanisms.
abstract: Extracellular adenosine mediates diverse anti-inflammatory, angiogenic, and other signaling effects via binding to adenosine receptors, and it also regulates cell proliferation and death via activation of the intrinsic signaling pathways. Given the emerging role of adenosine and other purines in tumor growth and metastasis, this study evaluated the effects of adenosine on the invasion of metastatic prostate and breast cancer cells. Treatment with low micromolar concentrations of adenosine, but not other nucleosides or adenosine receptor agonists, inhibited subsequent cell invasion and migration through Matrigel- and laminin-coated inserts. These inhibitory effects occurred via intrinsic receptor-independent mechanisms, despite the abundant expression of A2B adenosine receptors (ADORA2B). Extracellular nucleotides and adenosine were shown to be rapidly metabolized on tumor cell surfaces via sequential ecto-5'-nucleotidase (CD73/NT5E) and adenosine deaminase reactions with subsequent cellular uptake of nucleoside metabolites and their intracellular interconversion into ADP/ATP. This was accompanied by concurrent inhibition of AMP-activated protein kinase and other signaling pathways. No differences in the proliferation rates, cytoskeleton assembly, expression of major adhesion molecules [integrin-1β (ITGB1), CD44, focal adhesion kinase], and secretion of matrix metalloproteinases were detected between the control and treated cells, thus excluding the contribution of these components of invasion cascade to the inhibitory effects of adenosine. These data provide a novel insight into the ability of adenosine to dampen immune responses and prevent tumor invasion via two different, adenosine receptor-dependent and -independent mechanisms.
  
  
  CONCLUSIONS
  This study suggests that the combined targeting of adenosine receptors and modulation of intracellular purine levels can affect tumor growth and metastasis phenotypes.
authors: Turku University of Applied Sciences, University of Turku, Turku, Finland. Department of Cell Biology and Anatomy, University of Turku, Turku, Finland.
authors: Sanna S
authors: SS
authors: Virtanen
authors: Department of Medical Microbiology, University of Turku, Turku, Finland.
authors: Anu
authors: A
authors: Kukkonen-Macchi
authors: Department of Biology, University of Turku, Turku, Finland.
authors: Minna
authors: M
authors: Vainio
authors: Department of Medical Microbiology, University of Turku, Turku, Finland.
authors: Kati
authors: K
authors: Elima
authors: Department of Cell Biology and Anatomy, University of Turku, Turku, Finland.
authors: Pirkko L
authors: PL
authors: Härkönen
authors: Department of Medical Microbiology, University of Turku, Turku, Finland.
authors: Sirpa
authors: S
authors: Jalkanen
authors: Department of Medical Microbiology, University of Turku, Turku, Finland. genyeg@utu.fi.
authors: Gennady G
authors: GG
authors: Yegutkin
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D000241:Adenosine