The A2B 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.