A3 ADENOSINE RECEPTORS MODULATE HYPOXIA-INDUCIBLE FACTOR-1ALPHA EXPRESSION IN HUMAN CANCER CELLS

Hypoxia appears to induce a program which shifts the cellular phenotype toward an increase in intracellular adenosine. Hypoxia-inducible factor-1 (HIF-1) is a key regulator of genes crucial to many aspects of cancer biology (1). Since the levels of both HIF-1 and adenosine are elevated within the hypoxic environment of solid tumors, we investigated whether adenosine may regulate HIF-1. In particular, we investigated the effect of A3 receptor antagonists on HIF-1 and vascular endothelial growth factor expression (2-5). The response to adenosine was generated at the cell surface because the inhibition of A3 receptor expression, by using small interfering RNA, abolished nucleoside effects. Furthermore, we characterized the signaling pathways induced by A3 receptors in hypoxia and provide results of how human tumor growth may be influenced through the adenosinergic system (6). (1) Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003, 3, 721–732. (2) Merighi, S.; Benini, A.; Mirandola, P.; Gessi, S.; Varani, K.; Simioni, C.; Leung, E.; Maclennan, S.; Baraldi, P.G.; Borea, P.A. Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells. Mol Pharmacol. 2007, 72, 395-406. (3) Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, Maclennan S, Baraldi, P.G.; Borea PA. Hypoxia inhibits paclitaxel-induced apoptosis through adenosine-mediated phosphorylation of bad in glioblastoma cells. Mol Pharmacol. 2007, 72, 162-72. (4) Merighi, S.; Benini, A.; Mirandola, P.; Gessi, S.; Varani, K.; Leung, E.; Maclennan, S.; Borea, P.A. Adenosine modulates vascular endothelial growth factor expression via hypoxia-inducible factor-1 in human glioblastoma cells. Biochem Pharmacol. 2006, 72, 19-31. (5) Merighi, S.; Benini, A.; Mirandola, P.; Gessi, S.; Varani, K.; Leung, E.; Maclennan, S.; Baraldi, P.G.; Borea, P.A. A3 adenosine receptors modulate hypoxia-inducible factor-1alpha expression in human A375 melanoma cells. Neoplasia 2005, 7, 894-903. (6) Merighi S.; Benini A.; Mirandola P.; Gessi S.; Varani K.; Leung E.; Maclennan S.; Borea PA. A3 adenosine receptor activation inhibits cell proliferation via phosphatidylinositol 3-kinase/Akt-dependent inhibition of the extracellular signal-regulated kinase 1/2 phosphorylation in A375 human melanoma cells. J Biol Chem. 2005, 280, 19516-26.