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Mammalian Target of Rapamycin 2 (MTOR2) and C-MYC Modulate Glucosamine-6-Phosphate Synthesis in Glioblastoma (GBM) Cells Through Glutamine: Fructose-6-Phosphate Aminotransferase 1 (GFAT1)

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An Expression of Concern to this article was published on 01 October 2019

A Correction to this article was published on 14 August 2019

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Abstract

Glucose and glutamine are two essential ingredients for cell growth. Glycolysis and glutaminolysis can be linked by glutamine: fructose-6-phosphate aminotransferase (GFAT, composed of GFAT1 and GFAT2) that catalyzes the synthesis of glucosamine-6-phosphate and glutamate by using fructose-6-phosphate and glutamine as substrates. The role of mammalian target of rapamycin (MTOR, composed of MTOR1 and MTOR2) in regulating glycolysis has been explored in human cancer cells. However, whether MTOR can interact with GFAT to regulate glucosamine-6-phosphate is poorly understood. In this study, we report that GFAT1 is essential to maintain the malignant features of GBM cells. And MTOR2 rather than MTOR1 plays a robust role in promoting GFAT1 protein activity, and accelerating the progression of glucosamine-6-phosphate synthesis, which is not controlled by the PI3K/AKT signaling. Intriguingly, high level of glucose or glutamine supply promotes MTOR2 protein activity. In turn, up-regulating glycolytic and glutaminolytic metabolisms block MTOR dimerization, enhancing the release of MTOR2 from the MTOR complex. As a transcriptional factor, C-MYC, directly targeted by MTOR2, promotes the relative mRNA expression level of GFAT1. Notably, our data reveal that GFAT1 immunoreactivity is positively correlated with the malignant grades of glioma patients. Kaplan–Meier assay reveals the correlations between patients’ 5-year survival and high GFAT1 protein expression. Taken together, we propose that the MTOR2/C-MYC/GFAT1 axis is responsible for the modulation on the crosstalk between glycolysis and glutaminolysis in GBM cells. Under the condition of accelerated glycolytic and/or glutaminolytic metabolisms, the MTOR2/C-MYC/GFAT1 axis will be up-regulated in GBM cells.

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Change history

  • 07 June 2019

    A correction has been published.

  • 14 August 2019

    The original version of this article unfortunately contained an error in author group. The authors Yi-Xiang See, Xin Chen, Zi-Kai Chen and Ze-Bin Huang were inadvertently included in the article.

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Acknowledgements

We thank Dr. Qi Zhang (Tiantan Hospital, Beijing, China) for kindly collecting glioma tissue samples and clinical information. This research was funded by the Postdoctoral Research Foundation (2014) provided by the University of Macau, SAR, China.

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Authors and Affiliations

  1. Laboratory of Molecular Genetics, University of Maryland School of Medicine, Baltimore, 21021, USA

    Bo Liu

  2. Department of Otorhinolaryngology Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, 21021, USA

    Bo Liu

  3. Center of Reproduction, development and aging, Institute of Translational Medicine, Cancer Centre, Faculty of Health Sciences, University of Macau, Hengqin, 999078, Macau, SAR, China

    Bo Liu, Ze-Bin Huang, Xin Chen, Yi-Xiang See, Zi-Kai Chen & Huan-Kai Yao

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Contributions

B.L. designed the research project, performed most of the experiments, analyzed the data, and wrote the manuscript. Z.B.H, X.C., Y.X.S., Z.K.C., and H.K.Y. performed the experiments and analyzed the data.

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Correspondence to Bo Liu.

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The authors declare that they have no conflicts of interest.

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This study used human glioma tissues and brain injury tissues obtained from Tiantan Hospital (Beijing, China). All procedures performed in studies involving human participants were in accordance with the Ethical Standards of the Institutional and/or National Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Liu, B., Huang, ZB., Chen, X. et al. Mammalian Target of Rapamycin 2 (MTOR2) and C-MYC Modulate Glucosamine-6-Phosphate Synthesis in Glioblastoma (GBM) Cells Through Glutamine: Fructose-6-Phosphate Aminotransferase 1 (GFAT1). Cell Mol Neurobiol 39, 415–434 (2019). https://doi.org/10.1007/s10571-019-00659-7

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