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.
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