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.