Several recent studies have shown evidence supporting the general knowledge that tumour cells exhibit changes in metabolism. It is becoming increasingly important to understand how these metabolic changes in tumour cells promote
carcinogenesis and
disease progression. We recently discovered a lack of
methylthioadenosine phosphorylase (MTAP) expression in
melanoma, which resulted in an accumulation of the metabolite
5'-methylthioadenosine (
MTA) in
melanoma cells and in the extracellular environment.
MTA was shown to affect cell proliferation of surrounding stroma cells and cell invasiveness and the activation of the
transcription factor activator protein-1 (AP-1) in
melanoma cells. In this study, we addressed the regulation of cellular signalling by extracellular
MTA accumulation. By focusing on putative receptors that could modulate
MTA signalling, we identified the
adenosine receptor ADORA2B as an important candidate. Knockdown experiments and the use of specific agonists and antagonists confirmed a link between
MTA and
AP-1 signalling through the ADORA2B receptor. Interestingly, stimulation of the cells with
MTA did not result in activation of the classical cyclic
adenosine monophosphate (cAMP) signalling cascades or in Ca(2+)-dependent signalling. We instead showed
protein kinase C (PKC) signalling to be involved in
MTA-mediated
AP-1 activation. In summary, we identified ADORA2B to be the specific receptor and signalling pathway for the metabolite
MTA. These findings may influence the use of
MTA in a therapeutic manner.