Adenosine (Ado) regulates a wide variety of physiological processes interacting with one or more of four known cell-surface receptors named A1, A2A, A2B and A3. The development of potent A3 agonists and selective antagonists revealed that the A3 subtype plays a pivotal role in the ado-induced modulation of tumor cells biology and the A3 subtype has been found up-regulated in cancer.1,2 Local invasive growth is one of the key features of primary brain tumors and metalloproteinases (MMPs) play a major role in promoting tumor metastasis. The involvement of ado in the regulation of MMP-9 in tumor cells have not been investigated by now. In this work, we investigated the biological functions of adenosine (ado) in metalloproteinase-9 (MMP-9) regulation in U87MG human glioblastoma cells. The nucleoside was able to increase both MMP-9 mRNA and protein levels through A3 receptors activation. We revealed that A3 receptor induced an increase of MMP-9 protein levels by phosphorylation of extracellular signal-regulated protein kinase (ERK1/2), c-Jun N-terminal kinase/stress-activated protein kinase (pJNK/SAPK), protein kinase B (Akt/PKB) and finally activator protein 1 (AP-1). A3 receptor activation stimulated also an increase of MMP-9 secretion and activity in supernatants from U87MG glioblastoma cells. Finally, the Matrigel invasion assay demonstrated that A3 receptors, by inducing an increase in MMP-9 levels, was responsible for an increase of glioblastoma cells invasion. Collectively, these results suggest for the first time that ado, through A3 receptors activation, modulates MMP-9 protein levels and plays a role in inducing invasion of U87MG cells. (1) Gessi, S.; Merighi, S.; Varani, K.; Leung, E.; Mac Lennan, S.; Borea, P.A. The A3 adenosine receptor: an enigmatic player in cell biology. Pharmacol. Ther. 2008, 117, 123-40. (2) Gessi, S.; Cattabriga, E.; Avitabile, A.; Gafa', R.; Lanza, G.; Cavazzini, L.; Bianchi, N.; Gambari, R.; Feo, C.; Liboni, A.; Gullini, S.; Leung, E.; Mac-Lennan, S.; Borea, P.A. Elevated expression of A3 adenosine receptors in human colorectal cancer is reflected in peripheral blood cells. Clin. Cancer Res. 2004, 10, 5895-901.
MODULATION OF MMP-9 IN U87MG GLIOBLASTOMA CELLS BY A3 ADENOSINE RECEPTORS
GESSI, Stefania;SACCHETTO, Valeria;FOGLI, Eleonora;MERIGHI, Stefania;VARANI, Katia;BARALDI, Pier Giovanni;AGHAZADEH TABRIZI, Mojgan;BOREA, Pier Andrea
2009
Abstract
Adenosine (Ado) regulates a wide variety of physiological processes interacting with one or more of four known cell-surface receptors named A1, A2A, A2B and A3. The development of potent A3 agonists and selective antagonists revealed that the A3 subtype plays a pivotal role in the ado-induced modulation of tumor cells biology and the A3 subtype has been found up-regulated in cancer.1,2 Local invasive growth is one of the key features of primary brain tumors and metalloproteinases (MMPs) play a major role in promoting tumor metastasis. The involvement of ado in the regulation of MMP-9 in tumor cells have not been investigated by now. In this work, we investigated the biological functions of adenosine (ado) in metalloproteinase-9 (MMP-9) regulation in U87MG human glioblastoma cells. The nucleoside was able to increase both MMP-9 mRNA and protein levels through A3 receptors activation. We revealed that A3 receptor induced an increase of MMP-9 protein levels by phosphorylation of extracellular signal-regulated protein kinase (ERK1/2), c-Jun N-terminal kinase/stress-activated protein kinase (pJNK/SAPK), protein kinase B (Akt/PKB) and finally activator protein 1 (AP-1). A3 receptor activation stimulated also an increase of MMP-9 secretion and activity in supernatants from U87MG glioblastoma cells. Finally, the Matrigel invasion assay demonstrated that A3 receptors, by inducing an increase in MMP-9 levels, was responsible for an increase of glioblastoma cells invasion. Collectively, these results suggest for the first time that ado, through A3 receptors activation, modulates MMP-9 protein levels and plays a role in inducing invasion of U87MG cells. (1) Gessi, S.; Merighi, S.; Varani, K.; Leung, E.; Mac Lennan, S.; Borea, P.A. The A3 adenosine receptor: an enigmatic player in cell biology. Pharmacol. Ther. 2008, 117, 123-40. (2) Gessi, S.; Cattabriga, E.; Avitabile, A.; Gafa', R.; Lanza, G.; Cavazzini, L.; Bianchi, N.; Gambari, R.; Feo, C.; Liboni, A.; Gullini, S.; Leung, E.; Mac-Lennan, S.; Borea, P.A. Elevated expression of A3 adenosine receptors in human colorectal cancer is reflected in peripheral blood cells. Clin. Cancer Res. 2004, 10, 5895-901.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
