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MYCN-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma

  • MYCN is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of MYC family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of MYC proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of MYCN overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of MYCN induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of MYCN. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts inMYCN is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of MYC family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of MYC proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of MYCN overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of MYCN induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of MYCN. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of MYCN overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered MYCN induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.zeige mehrzeige weniger

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Metadaten
Autoren/innen:B. Tjaden, K. Baum, V. Marquardt, M. Simon, M. Trajkovic-Arsic, T. Kouril, B. Siebers, Jan Lisec, J. T. Siveke, J. H. Schulte, U. Benary, M. Remke, J. Wolf, A. Schramm
Dokumenttyp:Zeitschriftenartikel
Veröffentlichungsform:Graue Literatur
Sprache:Englisch
Titel des übergeordneten Werkes (Englisch):bioRxiv : The preprint server for biology
Jahr der Erstveröffentlichung:2018
Organisationseinheit der BAM:1 Analytische Chemie; Referenzmaterialien
1 Analytische Chemie; Referenzmaterialien / 1.7 Organische Spuren- und Lebensmittelanalytik
Verlag:Cold Spring Harbor Laboratory
Verlagsort:Cold Spring Harbor, NY
Erste Seite:1
Letzte Seite:21
DDC-Klassifikation:Naturwissenschaften und Mathematik / Chemie / Analytische Chemie
Freie Schlagwörter:MYCN; Mass-spectrometry; Tumor metabolism
Themenfelder/Aktivitätsfelder der BAM:Analytical Sciences
Analytical Sciences / Spurenanalytik und chemische Zusammensetzung
DOI:https://doi.org/10.1101/423756
Verfügbarkeit des Dokuments:Datei im Netzwerk der BAM verfügbar ("Closed Access")
Datum der Freischaltung:30.11.2018
Referierte Publikation:Nein