Myc promotes glutaminolysis in human neuroblastoma through direct activation of glutaminase 2
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// Daibiao Xiao 1 , Ping Ren 2 , Hexiu Su 3 , Ming Yue 1 , Ruijuan Xiu 1 , Yufeng Hu 3 , Hudan Liu 3, 4 , Guoliang Qing 1, 4 1 School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China 2 Department of Pharmacology, School of Pharmacy, Hubei University of Science & Technology, Xianning 437100, China 3 School of Pharmacy, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China 4 Medical Research Institute, Wuhan University, Wuhan 430071, China Correspondence to: Guoliang Qing, e-mail: qingguoliang@whu.edu.cn Keywords: neuroblastoma, N-Myc, glutaminase 2, glutamine, cancer metabolism Received: May 09, 2015 Accepted: September 23, 2015 Published: October 19, 2015 ABSTRACT Deamidation of glutamine to glutamate by glutaminase 1 (GLS1, also called GLS) and GLS2 is an essential step in both glutaminolysis and glutathione (GSH) biosynthesis. However, mechanisms whereby cancer cells regulate glutamine catabolism remains largely unknown. We report here that N-Myc, an essential Myc family member, promotes conversion of glutamine to glutamate in MYCN -amplified neuroblastoma cells by directly activating GLS2, but not GLS1, transcription. Abrogation of GLS2 function profoundly inhibited glutaminolysis, which resulted in feedback inhibition of aerobic glycolysis likely due to thioredoxin-interacting protein (TXNIP) activation, dramatically decreasing cell proliferation and survival in vitro and in vivo . Moreover, elevated GLS2 expression is significantly elevated in MYCN -amplified neuroblastomas in comparison with non-amplified ones, correlating with unfavorable patient survival. In aggregate, these results reveal a novel mechanism deciphering context-dependent regulation of metabolic heterogeneities, uncovering a previously unsuspected link between Myc, GLS2 and tumor metabolism.
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CHK1 inhibitors and glutaminase inhibitors are considered potential candidates for treating Myc-overexpressing cancers.
“Similarly, checkpoint kinase 1 (CHK1) inhibitors625–627 and glutaminase (GLS) inhibitors628–634 are also considered potential candidates for treating Myc-overexpressing cancers.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [633]
MYC-driven cancer cells exhibit enhanced glutamine utilization with increased expression of GLS1/GLS2 and GLUD1.
“MYC-driven cancer cells exhibit enhanced glutamine utilization accompanied by increased expression of key glutaminolysis enzymes, including GLS1/GLS2 and GLUD1178–180.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [180]
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- Authors
- Xiao, D., Ren, P., Su, H., Yue, M., Xiu, R., Hu, Y., Liu, H., & Qing, G.
- Affiliations
- Huazhong University of Science and Technology (CN)
- Hubei University of Science and Technology (CN)
- Wuhan University (CN)
- Corresponding author
- Qing, Guoliang
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2015-10-19
- Volume
- 6
- Issue
- 38
- Pages
- 40655-40666
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC4747359
- OpenAlex
- W2269870164
- Cited by
- 80
- References
- 32
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 10 · 2021: 5 · 2020: 15 · 2019: 6 · 2018: 7 · 2017: 11 · 2016: 8
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81572736, 81372205, 81171928, 81200381)
- Huazhong University of Science and Technology (2014ZHYX002)
- Topics
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- MYCN, GLS2, glutaminolysis, neuroblastoma, MYCN amplification, glutamine metabolism, glutathione synthesis, TXNIP, aerobic glycolysis, cancer metabolism, cell proliferation
- MeSH terms
- Animals, Enzyme Activation, Glutaminase, Glutamine, Glycolysis, Humans, Hydrolysis, Immunoenzyme Techniques, Neuroblastoma, RNA, Messenger, Tumor Cells, Cultured, Blotting, Western, Proto-Oncogene Proteins c-myc, Mice, SCID, Mice, Inbred NOD, Apoptosis, Reverse Transcriptase Polymerase Chain Reaction, Xenograft Model Antitumor Assays, Chromatin Immunoprecipitation, Cell Proliferation, Mice, Real-Time Polymerase Chain Reaction
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