title: The metabolite 5'-methylthioadenosine signals through the adenosine receptor A2B in melanoma.
abstract: 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.
authors.affiliation: Institute of Pathology, University of Regensburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Limm
authors.affiliation: Institute of Pathology, University of Regensburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Wallner
authors.affiliation: Molecular Neurosciences, Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Milenkovic
authors.affiliation: Molecular Neurosciences, Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.
authors.forename: Christian H
authors.initials: CH
authors.lastname: Wetzel
authors.affiliation: Institute of Pathology, University of Regensburg, Germany. Electronic address: anja.bosserhoff@klinik.uni-regensburg.de.
authors.forename: Anja-Katrin
authors.initials: AK
authors.lastname: Bosserhoff
mesh_terms: D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003839:Deoxyadenosines / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013872:Thionucleosides / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D003839:Deoxyadenosines; D043704:Receptor, Adenosine A2B; D013872:Thionucleosides; D018808:Transcription Factor AP-1; C008500:5'-methylthioadenosine; D011493:Protein Kinase C; D002118:Calcium
keywords: 5′-Methylthioadenosine; AP-1-trascription factor; Adenosine receptor A2B; CREB-1 pathway; MAPK/ERK – PKC signalling; Melanoma