The Function of GPT2 in Tumor Progression

Glutamate pyruvate transaminase 2 (GPT2) is one of the GPTs and is widely used as a biomarker of hepatocellular injury, along with GPT1. GPT2, a glutamine-metabolizing transaminase found in mitochondria, catalyzes the reversible process between glutamate, pyruvate, α-ketoglutarate, and alanine. Compared to GPT1, the intracellular abundance of GPT2 is higher, suggesting that its enzymatic activity has a considerable role in glucose metabolism, amino acid metabolism, and lipid metabolism. In recent years, it has been discovered that deletion or mutation of GPT2 causes malignant transformation of tumors and that its expression level is closely correlated with tumor development. It is for this reason that the level of GPT2 can be used to reflect the metabolism level of the tumor cells in the body and can indicate metastasis based on its changes. The metabolism level of GPT2 in tumor cells is expected to be a marker in the tumor diagnostic process and subsequently contribute to early detection, thus improving tumor diagnosis and patient prognosis. This paper presents an overview of the current state of GPT2 research in the progression of tumors.
Mirestean CC, Iancu RI, Iancu D, 2022, New Horizons in Modulating the Radio-sensitivity of Head and Neck Cancer-100 Years after Warburg’ Effect Discovery. Front Oncol, 12:908695. DOI: 10.3389/fonc.2022.908695
Kao TW, Chuang YC, Lee HL, et al., 2022, Therapeutic Targeting of Glutaminolysis as a Novel Strategy to Combat Cancer Stem Cells. Int J Mol Sci, 23:15296. DOI: 10.3390/ijms232315296
Niklison-Chirou MV, Erngren I, Engskog M, et al., 2017, TAp73 is a Marker of Glutamine Addiction in Medulloblastoma. Genes Dev, 31:1738–53. DOI: 10.1101/gad.302349.117
Yang L, Venneti S, Nagrath D, 2017, Glutaminolysis: A Hallmark of Cancer Metabolism. Annu Rev Biomed Eng, 19:163–94. DOI: 10.1146/annurev-bioeng-071516-044546
Li T, Le A, 2018, Glutamine Metabolism in Cancer. Adv Exp Med Biol, 1063:13–32. DOI: 10.1007/978-3-319-77736-8_2
Cicatiello AG, Sagliocchi S, Nappi A, et al., 2022, Thyroid Hormone Regulates Glutamine Metabolism and Anaplerotic Fluxes by Inducing Mitochondrial Glutamate Aminotransferase GPT2. Cell Rep, 38:110409. DOI: 10.1016/j.celrep.2022.110409
Kim M, Gwak J, Hwang S, et al., 2019, Mitochondrial GPT2 Plays a Pivotal Role in Metabolic Adaptation to the Perturbation of Mitochondrial Glutamine Metabolism. Oncogene, 38:4729–38. DOI: 10.1038/s41388-019-0751-4
Sajnani K, Islam F, Smith RA, et al., 2017, Genetic Alterations in Krebs Cycle and Its Impact on Cancer Pathogenesis. Biochimie, 135:164–72. DOI: 10.1016/j.biochi.2017.02.008
Luengo A, Gui DY, Heiden MG, 2017, Targeting Metabolism for Cancer Therapy. Cell Chem Biol, 24:1161–80. DOI: 10.1016/j.chembiol.2017.08.028
Zhao H, Wu W, Li X, et al., 2022, Long Noncoding RNA UCA1 Promotes Glutamine-driven Anaplerosis of Bladder Cancer by Interacting with hnRNP I/L to Upregulate GPT2 Expression. Transl Oncol, 17:101340. DOI: 10.1016/j.tranon.2022.10134
Gondas E, Hives M, Kliment J, et al., 2022, The Ubiquitous Expression of Pyruvate Carboxylase among Human Prostate Tumors. Bratisl Lek Listy, 123:487–90. DOI: 10.4149/BLL_2022_077
Bernfeld E, Foster DA, 2019, Glutamine as an Essential Amino Acid for KRas-Driven Cancer Cells. Trends Endocrinol Metab, 30:357–68. DOI: 10.1016/j.tem.2019.03.003
Bodineau C, Tomé M, Murdoch PD, et al., 2022, Glutamine, MTOR and Autophagy: A Multiconnection Relationship. Autophagy, 18:2749–50. DOI: 10.1080/15548627.2022.2062875
Yang X, Li Z, Ren H, et al., 2022, New Progress of Glutamine Metabolism in the Occurrence, Development, and Treatment of Ovarian Cancer from Mechanism to Clinic. Front Oncol, 12:1018642. DOI: 10.3389/fonc.2022.1018642
Kodama M, Oshikawa K, Shimizu H, et al., 2020, A Shift in Glutamine Nitrogen Metabolism Contributes to the Malignant Progression of Cancer. Nat Commun, 11:1320. DOI: 10.1038/s41467-020-15136-9
Hakvoort TB, He Y, Kulik W, et al., 2017, Pivotal Role of Glutamine Synthetase in Ammonia Detoxification. Hepatology, 65:281–93. DOI: 10.1002/hep.28852
Soria LR, Nitzahn M, De Angelis A, et al., 2019, Hepatic Glutamine Synthetase Augmentation Enhances Ammonia Detoxification. J Inherit Metab Dis, 42:1128–35. DOI: 10.1002/jimd.12070
Mukherjee A, Ahmed N, Rose FT, et al., 2020, Asparagine Synthetase is Highly Expressed at Baseline in the Pancreas through Heightened PERK Signaling. Cell Mol Gastroenterol Hepatol, 9:1–13. DOI: 10.1016/j.jcmgh.2019.08.003
Fan S, Wang Y, Zhang Z, et al., 2018, High Expression of Glutamate-ammonia Ligase is Associated with Unfavorable Prognosis in Patients with Ovarian Cancer. J Cell Biochem, 119:6008–15. DOI: 10.1002/jcb.26797
Moudi B, Heidari Z, Mahmoudzadeh-Sagheb H, et al., 2018, Concomitant Use of Heat-shock Protein 70, Glutamine Synthetase and Glypican-3 is Useful in Diagnosis of HBV-related Hepatocellular Carcinoma with Higher Specificity and Sensitivity. Eur J Histochem, 62:2859. DOI: 10.4081/ejh.2018.2859
Ye J, Huang Q, Xu J, et al., 2018, Targeting of Glutamine Transporter ASCT2 and Glutamine Synthetase Suppresses Gastric Cancer Cell Growth. J Cancer Res Clin Oncol, 144: 821–33. DOI: 10.1007/s00432-018-2605-9
Eelen G, Dubois C, Cantelmo AR, et al., 2018, Role of Glutamine Synthetase in Angiogenesis Beyond Glutamine Synthesis. Nature, 561:63–9. DOI: 10.1038/s41586-018-0466-7
Palmieri EM, Menga A, Martín-Pérez R, et al., 2017, Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis. Cell Rep, 20:1654–66. DOI: 10.1016/j.celrep.2017.07.054
Matés JM, Di Paola FJ, Campos-Sandoval JA, et al., 2020, Therapeutic Targeting of Glutaminolysis as an Essential Strategy to Combat Cancer. Semin Cell Dev Biol, 98:34–43. DOI: 10.1016/j.semcdb.2019.05.012
Katt WP, Lukey MJ, Cerione RA, 2017, A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis. Future Med Chem, 9:223–43. DOI: 10.4155/fmc-2016-0190
Cluntun AA, Lukey MJ, Cerione RA, et al., 2017, Glutamine Metabolism in Cancer: Understanding the Heterogeneity. Trends Cancer, 3:169–80. DOI: 10.1016/j.trecan.2017.01.005
Sengupta D, Cassel T, Teng KY, et al., 2020, Regulation of Hepatic Glutamine Metabolism by miR-122. Mol Metab, 34:174–86. DOI: 10.1016/j.molmet.2020.01.003
Zhang J, Wang L, Mao S, et al., 2018, miR-1-3p Contributes to Cell Proliferation and Invasion by Targeting Glutaminase in Bladder Cancer Cells. Cell Physiol Biochem, 51:513–27. DOI: 10.1159/00049527
Cao Y, Lin SH, Wang Y, et al., 2017, Glutamic Pyruvate Transaminase GPT2 Promotes Tumorigenesis of Breast Cancer Cells by Activating Sonic Hedgehog Signaling. Theranostics, 7:3021–33. DOI: 10.7150/thno.18992
Mitra D, Vega-Rubin-de-Celis S, Royla N, et al., 2021, Abrogating GPT2 in Triple-negative Breast Cancer Inhibits Tumor Growth and Promotes Autophagy. Int J Cancer, 148:1993–2009. DOI: 10.1002/ijc.33456
Xu P, Oosterveer MH, Stein S, et al., 2016, LRH-1- dependent Programming of Mitochondrial Glutamine Processing Drives Liver Cancer. Genes Dev, 30:1255–60. DOI: 10.1101/gad.277483.11
Wang R, Xiang W, Xu Y, et al., 2020, Enhanced Glutamine Utilization Mediated by SLC1A5 and GPT2 is an Essential Metabolic Feature of Colorectal Signet Ring Cell Carcinoma with Therapeutic Potential. Ann Transl Med, 8:302. DOI: 10.21037/atm.2020.03.31
Chen W, Dai G, Qian Y, et al., 2022, PIK3CA Mutation Affects the Proliferation of Colorectal Cancer Cells through the PI3K-MEK/PDK1-GPT2 Pathway. Oncol Rep, 47:11. DOI: 10.3892/or.2021.8222
Caiola E, Colombo M, Sestito G, et al., 2020, Glutaminase Inhibition on NSCLC Depends on Extracellular Alanine Exploitation. Cells, 9:1766. DOI: 10.3390/cells9081766
Wu J, Miao C, Wang Y, et al., 2022, SPTBN1 Abrogates Renal Clear Cell Carcinoma Progression Via Glycolysis Reprogramming in a GPT2-Dependent Manner. J Transl Med, 20:603. DOI: 10.1186/or.2022.12.16
Franco YE, Alves MJ, et al., 2021, Glutaminolysis Dynamics During Astrocytoma Progression Correlates with Tumor Aggressiveness. Cancer Metab, 9:18. DOI: 10.1186/or.2021.04.28