Role of 5'-methylthioadenosine in tumor progression
Final Report Abstract
Several 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. In our project, integrated into the KFO262 (first funding period), we 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, cell invasiveness and the activation of the transcription factor activator protein-1 (AP-1) in melanoma cells. Further, 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. 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. In addition to signalling, MTA is a known inhibitor of protein arginine methyltransferases (PRMTs). Our findings demonstrated that general PRMT activity and, consequently, symmetric and asymmetric protein methylation are reduced significantly in melanoma cells and tissues. We could demonstrate that this is due to the loss of MTAP expression and accumulation of MTA. In summary, supported by the funding in the KFO262 we revealed important effects of the accumulation of MTA on melanoma cell signalling and activity.
Publications
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(2012): A seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue microarray study with two independent patient cohorts. PLoS One 7:e38222
Meyer S, Fuchs TJ, Bosserhoff AK, Hofstädter F, Pauer A, Roth V, Buhmann JM, Moll I, Anagnostou N, Brandner JM, Ikenberg K, Moch H, Landthaler M, Vogt T, Wild PJ
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(2013) Expression and function of methylthioadenosine phosphorylase in chronic liver disease. PLoS One 8(12):e80703
Czech B, Dettmer K, Valletta D, Saugspier M, Koch A, Stevens AP, Thasler WE, Müller M, Oefner PJ, Bosserhoff AK, Hellerbrand C
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(2013): Deregulation of protein methylation in melanoma. Eur J Cancer 49:1305-1313
Limm K, Ott C, Wallner S, Mueller DW, Oefner P, Hellerbrand C, Bosserhoff AK
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(2014): The metabolite 5'- methylthioadenosine signals through the adenosine receptor A2B in melanoma. Eur J Cancer 50(15):2714-24
Limm K, Wallner S, Milenkovic VM, Wetzel CH, Bosserhoff AK
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(2016): Characterization of the Methylthioadenosine Phosphorylase Polymorphism rs7023954 - Incidence and Effects on Enzymatic Function in Malignant Melanoma. PLoS One 11(8):e0160348
Limm K, Dettmer K, Reinders J, Oefner PJ, Bosserhoff AK
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(2016): Suppressive effects of tumor cell-derived 5'-deoxy-5'-methylthioadenosine on human T cells. Oncoimmunology 5(8):e1184802
Henrich FC, Singer K, Poller K, Bernhardt L, Strobl CD, Limm K, Ritter AP, Gottfried E, Völkl S, Jacobs B, Peter K, Mougiakakos D, Dettmer K, Oefner PJ, Bosserhoff AK, Kreutz MP, Aigner M, Mackensen A
