Abstract
It was previously shown that the estrogen-receptor negative breast cancer cell line MBA-MD-231 expresses high levels of A2B adenosine receptors as the sole adenosine receptor subtype. These receptors couple to both, stimulation of adenylyl cyclase and a Ca2+ signal. In order to establish a potential role of A2B adenosine receptors in tumor growth and development MAPK signaling was investigated in these breast cancer cells. Although it is known that A2B adenosine receptors may stimulate MAPK it was found that in MBA-MD-231 cells ERK1/2 phosphorylation is reduced upon agonist-stimulation of A2B 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 Ca2+ was established as the Ca2+ 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 A2B stimulation. It was shown that various pathways downstream from A2B 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 A2B adenosine receptors might provide an interesting approach for adjuvant treatment leading to reduced growth of certain tumors expressing the A2B subtype.
Highlights
Adenosine receptors (ARs) comprise a family of four G protein-coupled receptors which are identified as A1, A2A, A2B, and A3 subtypes [1, 2]
We have previously shown that MDA-MB 231 breast cancer cells express very high levels of A2B receptors as the sole adenosine receptor subtype [9]
The AR agonist 2-[p-(2-carboxyethyl) phenylethylamino]adenosine-5’-N-ethyluronamide (CGS 21680) that does not stimulate the A2B subtype, did not show any effect (Fig 1C). These data support the notion that the observed reduction of ERK1/2 phosphorylation was mediated by the A2B adenosine receptor
Summary
Adenosine receptors (ARs) comprise a family of four G protein-coupled receptors which are identified as A1, A2A, A2B, and A3 subtypes [1, 2]. Adenosine affects the function of virtually every organ due to abundant expression of one or several AR subtypes [1,2,3]. Increasing evidence suggests that adenosine may be involved in the regulation of cellular growth control and proliferation via all four receptor subtypes and, these may serve as therapeutic targets to combat tumor development and growth [5,6,7,8]
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