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ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.

ABSTRACT: Oncogenic Myc alters mitochondrial metabolism, making it dependent on exogenous glutamine (Gln) for cell survival. Accordingly, Gln deprivation selectively induces apoptosis in MYC-overexpressing cells via unknown mechanisms. Using MYCN-amplified neuroblastoma as a model, we identify PUMA, NOXA, and TRB3 as executors of Gln-starved cells. Gln depletion in MYC-transformed cells induces apoptosis through ATF4-dependent, but p53-independent, PUMA and NOXA induction. MYC-transformed cells depend on both glutamate-oxaloacetate transaminase and glutamate dehydrogenase to maintain Gln homeostasis and suppress apoptosis. Consequently, either ATF4 agonists or glutaminolysis inhibitors potently induce apoptosis in vitro and inhibit tumor growth in vivo. These results reveal mechanisms whereby Myc sensitizes cells to apoptosis, and validate ATF4 agonists and inhibitors of Gln metabolism as potential Myc-selective cancer therapeutics.

SUBMITTER: Qing G

PROVIDER: S-EPMC3510660 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.

Qing Guoliang G Li Bo B Li Bo B Vu Annette A Skuli Nicolas N Walton Zandra E ZE Liu Xueyuan X Mayes Patrick A PA Wise David R DR Thompson Craig B CB Maris John M JM Hogarty Michael D MD Simon M Celeste MC

Cancer cell 20121101 5

Oncogenic Myc alters mitochondrial metabolism, making it dependent on exogenous glutamine (Gln) for cell survival. Accordingly, Gln deprivation selectively induces apoptosis in MYC-overexpressing cells via unknown mechanisms. Using MYCN-amplified neuroblastoma as a model, we identify PUMA, NOXA, and TRB3 as executors of Gln-starved cells. Gln depletion in MYC-transformed cells induces apoptosis through ATF4-dependent, but p53-independent, PUMA and NOXA induction. MYC-transformed cells depend on ...[more]

PMID: 23153536

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Project description:Targeting glutamine metabolism has emerged as a potential therapeutic strategy for Myc overexpressing cancer cells. Myc proteins contribute to an aggressive neuroblastoma phenotype. Radiotherapy is one of the treatment modalities for high-risk neuroblastoma patients. Herein, we investigated the effect of glutamine deprivation in combination with irradiation in neuroblastoma cells representative of high-risk disease and studied the role of Myc member interplay in regulating neuroblastoma cell radioresistance. Methods: Cell proliferation and viability assays were used to establish the effect of glutamine deprivation in neuroblastoma cells expressing c-Myc or MycN. Gene silencing and overexpression were used to modulate the expression of Myc genes to determine their role in neuroblastoma radioresistance. qPCR and western blot investigated interplay between expression of Myc members. The impact of glutamine deprivation on cell response following irradiation was explored using a radiobiological 3D colony assay. DNA repair gene pathways as well as CSC-related genes were studied by qPCR array. Reactive Oxygen Species (ROS) and glutathione (GSH) levels were detected by fluorescence and luminescence probes respectively. Cancer-stem cell (CSC) properties were investigated by sphere-forming assay and flow cytometry to quantify CSC markers. Expression of DNA repair genes and CSC-related genes was analysed by mining publicly available patient datasets. Results: Our results showed that glutamine deprivation decreased neuroblastoma cell proliferation and viability and modulated Myc member expression. We then demonstrated for the first time that combined glutamine deprivation with irradiation led to a selective radioresistance of MYCN-amplified neuroblastoma cells. By exploring the underlying mechanism of neuroblastoma radioresistance properties, our results highlight interplay between c-Myc and MycN expression suggesting compensatory mechanisms in Myc proteins leading to radioresistance in MYCN-amplified cells. This result was associated with the ability of MYCN-amplified cells to dysregulate the DNA repair gene pathway, maintain GSH and ROS levels and to increase the CSC-like population and properties. Conversely, glutamine deprivation led to radiosensitization in non-MYCN amplified cell lines through a disruption of the cell redox balance and a trend to decrease in the CSC-like populations. Mining publicly available gene expression dataset obtained from pediatric neuroblastoma patients, we identified a correlation pattern between Myc members and CSC-related genes as well as a specific group of DNA repair gene pathways. Conclusions: This study demonstrated that MycN and c-Myc tightly cooperate in regulation of the neuroblastoma CSC phenotypes and radioresistance upon glutamine deprivation. Pharmacologically, strategies targeting glutamine metabolism may prove beneficial in Myc-driven tumors. Consideration of MycN/c-Myc status in selecting neuroblastoma patients for glutamine metabolism treatment will be important to avoid potential radioresistance.

Dataset Information

ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.

Publications

ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.

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