MYCN drives glutaminolysis in neuroblastoma and confers sensitivity to an ROS augmenting agent

Tingting Wang,Xuyong Chen,Jun Yang,Gaojian Lian,Andrew M Davidoff,Ruoning Wang,Lingling Liu,Yuqing Shen,Nilay Shah

doi:10.1038/s41419-018-0295-5

Abstract

Heightened aerobic glycolysis and glutaminolysis are characteristic metabolic phenotypes in cancer cells. Neuroblastoma (NBL), a devastating pediatric cancer, is featured by frequent genomic amplification of MYCN, a member of the Myc oncogene family that is primarily expressed in the early stage of embryonic development and required for neural crest development. Here we report that an enriched glutaminolysis gene signature is associated with MYCN amplification in children with NBL. The partial knockdown of MYCN suppresses glutaminolysis in NBL cells. Conversely, forced overexpression of MYCN in neural crest progenitor cells enhances glutaminolysis. Importantly, glutaminolysis induces oxidative stress by producing reactive oxygen species (ROS), rendering NBL cells sensitive to ROS augmentation. Through a small-scale metabolic-modulator screening, we have found that dimethyl fumarate (DMF), a Food and Drug Administration-approved drug for multiple sclerosis, suppresses NBL cell proliferation in vitro and tumor growth in vivo. DMF suppresses NBL cell proliferation through inducing ROS and subsequently suppressing MYCN expression, which is rescued by an ROS scavenger. Our findings suggest that the metabolic modulation and ROS augmentation could be used as novel strategies in treating NBL and other MYC-driven cancers.

Highlights

Heightened aerobic glycolysisand glutaminolysis are characteristic hallmarks of cancer cells[1,2,3,4,5]
It has been well recognized that the protooncogene, MYC, is responsible for orchestrating a transcriptional program driving metabolic reprogramming in many adult tumors, the role of MYC, its family member MYCN, during metabolic reprogramming in pediatric cancers including NBL is not fully understood
By cross-referencing the published microarray and genetic data, we found that an enriched glutaminolysis gene signature is associated with MYCN amplification in children with NBL (Fig. 1a)

Summary

Introduction

Glutaminolysis are characteristic hallmarks of cancer cells[1,2,3,4,5]. Both processes are tightly controlled to fulfill cell growth-associated and proliferation-associated bioenergetics, biosynthetic, and redox demands. Half of the patients with NBL are considered “high risk,” as defined by clinical, radiographic, and biological criteria. These patients have a high rate of treatment failure, most commonly due to disease progression early in treatment or relapse at the end of multimodal therapy. These failures make NBL the deadliest extracranial pediatric solid tumor, accounting

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