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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.
AuthorsKatharina Limm, Susanne Wallner, Vladimir M Milenkovic, Christian H Wetzel, Anja-Katrin Bosserhoff
JournalEuropean journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 50 Issue 15 Pg. 2714-24 (Oct 2014) ISSN: 1879-0852 [Electronic] England
PMID25087184 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References
  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Deoxyadenosines
  • Receptor, Adenosine A2B
  • Thionucleosides
  • Transcription Factor AP-1
  • 5'-methylthioadenosine
  • Protein Kinase C
  • Calcium
Topics
  • Blotting, Western
  • Calcium (metabolism)
  • Cell Line
  • Cell Line, Tumor
  • Cyclic AMP Response Element-Binding Protein (metabolism)
  • Deoxyadenosines (metabolism)
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Melanoma (genetics, metabolism, pathology)
  • Protein Kinase C (metabolism)
  • RNA Interference
  • Receptor, Adenosine A2B (genetics, metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Thionucleosides (metabolism)
  • Transcription Factor AP-1 (metabolism)

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