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

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.Myc proteins are encoded by a small family of proto-oncogenes consisting of MYC, MYCN and MYCL. In normal tissues, their expression is tightly regulated, while deregulation of MYC family members has been identified as a driving force in different cancer types. Since specific binding motifs, termed E-boxes, had been identified early on, Myc proteins were considered to be gene-specific transcription factors. This concept has been recently extended by different studies suggesting that deregulated Myc in tumors functions as a general transcriptional amplifier 1-3 . However, Myc-induced and tumor-specific mechanisms of target gene control on transcriptional level have only recently been addressed mechanistically 4 . The picture emerges that, at least in settings with vastly elevated Myc-levels, enhancer invasion by N-Myc and associated proteins contributes to tumor-specific N-Myc signatures. Moreover, the concept of Myc-mediated cell autonomous effects to boost tumor cell proliferation has been extended to include restriction of host immune reactions towards a tumor 5 . Although these efforts led to

MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma

“…System X c (−) imports cystine as a key substrate for synthesizing glutathione (GSH), which is the reducing equivalent used by GPX4 to antagonize ferroptosis 15 . Although MYCN has a role in regulating cellular redox balance 16 , the potential effects of MYCN on ferroptosis remain unclear.…”

Amino Acids Regulate Cisplatin Insensitivity in Neuroblastoma

“…Metabolic rewiring is an effective phenomenon opted by tumor cells in evading therapy response. Recent studies have demonstrated that oncogene-mediated metabolism augments tumor growth in neuroblastoma [ 24 ]. Direct metabolic dependencies of tumor cells are being explored to exploit these dependencies as novel therapeutic targets for sensitizing neuroblastoma to therapeutic agents [ 25 ].…”

“…Metabolic pathways involving amino acids also play key role in promoting cancer [ 29 ]. Metabolism of Serine, Glycine, Glutamine, and Tryptophan metabolites have been shown to promote cellular growth in neuroblastoma models [ 24 , 30 , 31 ]. Tumor cells maintain their amino pools through uptake of exogenous amino acids which is under tight regulation through cellular receptor expression and mechanistic Target of Rapamycin kinase (mTOR) [ 32 ].…”

Biological Role of MYCN in Medulloblastoma: Novel Therapeutic Opportunities and Challenges Ahead

“…Similar to its family members, MYCN is a potent regulator of cellular metabolism, through controlled expression of amino acid transporters and other proteins involved in aerobic glycolysis, oxidative phosphorylation, detoxification of reactive oxygen species (ROS), and fatty acid oxidation (175). While numerous studies have demonstrated a key role of MYCN in NB and GBM metabolism (176)(177)(178)(179)(180), its metabolic function in medulloblastoma still remains elusive. It is likely that in these tumours, as in other cancers, MYCN reconfigures metabolism to favour aerobic glycolysis and a dependency on the serineglycine-one-carbon (SGOC) to generate metabolic products starting from serine and glycine amino acids (181).…”