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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / pharmacology
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Allografts
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Child
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Dimethyl Fumarate / antagonists & inhibitors
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Dimethyl Fumarate / pharmacology*
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Drug Screening Assays, Antitumor
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Free Radical Scavengers / pharmacology
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Gene Expression Regulation, Neoplastic*
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Glutamine / agonists
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Glutamine / antagonists & inhibitors
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Glutamine / metabolism
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Glycolysis / drug effects
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Glycolysis / genetics
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Humans
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Mice
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N-Myc Proto-Oncogene Protein / antagonists & inhibitors
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N-Myc Proto-Oncogene Protein / genetics*
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N-Myc Proto-Oncogene Protein / metabolism
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Neural Crest / drug effects
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Neural Crest / metabolism
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Neural Crest / pathology
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Neuroblastoma / drug therapy
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Neuroblastoma / genetics*
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Neuroblastoma / metabolism
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Neuroblastoma / pathology
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Neurons / drug effects
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Neurons / metabolism
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Neurons / pathology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Reactive Oxygen Species / agonists
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism*
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Signal Transduction
Substances
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Antineoplastic Agents
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Free Radical Scavengers
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MYCN protein, human
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MYCN protein, mouse
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N-Myc Proto-Oncogene Protein
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RNA, Small Interfering
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Reactive Oxygen Species
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Glutamine
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Dimethyl Fumarate
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Acetylcysteine