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N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma

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Item Type:Article
Title:N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma
Creators Name:Tjaden, B. and Baum, K. and Marquardt, V. and Simon, M. and Trajkovic-Arsic, M. and Kouril, T. and Siebers, B. and Lisec, J. and Siveke, J.T. and Schulte, J.H. and Benary, U. and Remke, M. and Wolf, J. and Schramm, A.
Abstract:N-Myc 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 N-Myc overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of N-Myc 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 N-Myc. 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 N-Myc overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered N-Myc induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.
Keywords:Cell Proliferation, Glucosamine, Glucose, N-Myc Proto-Oncogene Protein, Neoplastic Gene Expression Regulation, Neuroblastoma, Tumor Cell Line
Source:Scientific Reports
Publisher:Nature Publishing Group
Page Range:7157
Date:28 April 2020
Official Publication:https://doi.org/10.1038/s41598-020-64040-1
PubMed:View item in PubMed
Related to:
https://edoc.mdc-berlin.de/17801/Preprint version

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