The A(2B) adenosine receptor in MDA-MB-231 breast cancer cells diminishes ERK1/2 phosphorylation by activation of MAPK-phosphatase-1

It was previously shown that the estrogen-receptor negative breast cancer cell line MBA-MD-231 expresses high levels of A(2B) adenosine receptors as the sole adenosine receptor subtype. These receptors couple to both, stimulation of adenylyl cyclase and a Ca(2+) signal. In order to establish a potential role of A(2B) adenosine receptors in tumor growth and development MAPK signaling was investigated in these breast cancer cells. Although it is known that A(2B) adenosine receptors may stimulate MAPK it was found that in MBA-MD-231 cells ERK1/2 phosphorylation is reduced upon agonist-stimulation of A(2B) adenosine receptors. This reduction is also triggered by forskolin, but abolished by the PKA inhibitor H89, suggesting an important role for the cAMP-PKA pathway. Likewise, a role for intracellular Ca(2+) was established as the Ca(2+) chelator 1,2-bis-(o-aminophenoxy)-ethane-N,N,N’,N’-tetraacetic acid, tetraacetoxymethyl ester (BAPTA-AM) abolished the reduction of ERK1/2 phosphorylation triggered by A(2B) stimulation. It was shown that various pathways downstream from A(2B) adenosine receptors resulted in a stimulation of MAPK phosphatase-1 (MKP-1) which dephosphorylates phospho ERK1/2, and thus plays a critical role in the regulation of the phosphorylation state of ERK1/2. The reduction of ERK1/2 phosphorylation mediated by A(2B) adenosine receptors might provide an interesting approach for adjuvant treatment leading to reduced growth of certain tumors expressing the A(2B) subtype.