Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer

Nguyen, Tu; Kirsch, Brian James; Asaka, Ryoichi; Nabi, Karim; Quinones, Addison; J, Tan; Antonio, Marjorie Justine; Camelo, Felipe; Li, Ting; Nguyen, Stephanie; Hoang, Giang; Nguyen, Kiet T.; Udupa, Sunag; Sazeides, Christos; Shen, Yao; Elgogary, Amira; Reyes, Juvenal; Zhao, Liang; Kleensang, André; Chaichana, Kaisorn L.; Hartung, Thomas; Betenbaugh, Michael J.; Marie, Suely Kazue Nagahashi; Jung, Jin Myung; Wang, Tian Li; Gabrielson, Edward; Le, Anne

doi:10.1016/j.celrep.2019.03.036

Cited by 79 publications

(87 citation statements)

References 50 publications

(82 reference statements)

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“…Among its many biochemical features, NAA, is particularly important for the maintenance of neuro-glial signaling [ 42 , 44 , 46 ]. NAA has been proposed to be an intermediate metabolite in the formation of the not fully elucidated neurotransmitter NAAG [ 42 , 44 , 47 ], although NAAG reaches maximally 10% of the NAA concentration [ 43 , 46 ]. Therefore, NAA is thought to have a more crucial function as a reservoir for glutamate [ 43 , 47 ], which is the most abundant neurotransmitter in the human brain [ 12 , 13 ].…”

Section: Magnetic Resonance Spectroscopymentioning

confidence: 99%

Current Methods of Magnetic Resonance for Noninvasive Assessment of Molecular Aspects of Pathoetiology in Multiple Sclerosis

Hnilicová

Štrbák

Kolísek

et al. 2020

IJMS

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Multiple sclerosis (MS) is an autoimmune disease with expanding axonal and neuronal degeneration in the central nervous system leading to motoric dysfunctions, psychical disability, and cognitive impairment during MS progression. The exact cascade of pathological processes (inflammation, demyelination, excitotoxicity, diffuse neuro-axonal degeneration, oxidative and metabolic stress, etc.) causing MS onset is still not fully understood, although several accompanying biomarkers are particularly suitable for the detection of early subclinical changes. Magnetic resonance (MR) methods are generally considered to be the most sensitive diagnostic tools. Their advantages include their noninvasive nature and their ability to image tissue in vivo. In particular, MR spectroscopy (proton 1H and phosphorus 31P MRS) is a powerful analytical tool for the detection and analysis of biomedically relevant metabolites, amino acids, and bioelements, and thus for providing information about neuro-axonal degradation, demyelination, reactive gliosis, mitochondrial and neurotransmitter failure, cellular energetic and membrane alternation, and the imbalance of magnesium homeostasis in specific tissues. Furthermore, the MR relaxometry-based detection of accumulated biogenic iron in the brain tissue is useful in disease evaluation. The early description and understanding of the developing pathological process might be critical for establishing clinically effective MS-modifying therapies.

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Section: Magnetic Resonance Spectroscopymentioning

confidence: 99%

Current Methods of Magnetic Resonance for Noninvasive Assessment of Molecular Aspects of Pathoetiology in Multiple Sclerosis

Hnilicová

Štrbák

Kolísek

et al. 2020

IJMS

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“…However, a recent study of melanoma has reported that intracellular P5C is rapidly converted to proline and thus glutamate production from this source is limited . Alternatively, the metabolite N ‐acetylaspartylglutamate has been shown to produce glutamate in pancreatic cancer both in vitro and in vivo via glutamate carboxypeptidase II (GCPII)‐catalyzed hydrolysis …”

mentioning

confidence: 99%

Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer

et al. 2019

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The targeting of glutamine metabolism specifically via pharmacological inhibition of glutaminase 1 (GLS1) has been translated into clinical trials as a novel therapy for several cancers. The results, though encouraging, show room for improvement in terms of tumor reduction. In this study, the glutaminase II pathway is found to be upregulated for glutamate production upon GLS1 inhibition in pancreatic tumors. Moreover, genetic suppression of glutamine transaminase K (GTK), a key enzyme of the glutaminase II pathway, leads to the complete inhibition of pancreatic tumorigenesis in vivo unveiling GTK as a new metabolic target for cancer therapy. These results suggest that current trials using GLS1 inhibition as a therapeutic approach targeting glutamine metabolism in cancer should take into account the upregulation of other metabolic pathways that can lead to glutamate production; one such pathway is the glutaminase II pathway via GTK.

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“…NAAG’s function as a neurotransmitter has been studied extensively. Recent research uncovered that NAAG serves as a glutamate source for tumor and lymphoma cells [ 36 ]. While it is well appreciated that amino acids and free fatty acids released during sepsis may serve as nutrients to immune cells, the role of NAAG or the converting enzyme glutamate carboxypeptidase II has not been studied so far.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling Reveals Distinct and Mutual Effects of Diet and Inflammation in Shaping Systemic Metabolism in Ldlr−/− Mice

2020

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Changes in modern dietary habits such as consumption of Western-type diets affect physiology on several levels, including metabolism and inflammation. It is currently unclear whether changes in systemic metabolism due to dietary interventions are long-lasting and affect acute inflammatory processes. Here, we investigated how high-fat diet (HFD) feeding altered systemic metabolism and the metabolomic response to inflammatory stimuli. We conducted metabolomic profiling of sera collected from Ldlr−/− mice on either regular chow diet (CD) or HFD, and after an additional low-dose lipopolysaccharide (LPS) challenge. HFD feeding, as well as LPS treatment, elicited pronounced metabolic changes. HFD qualitatively altered the systemic metabolic response to LPS; particularly, serum concentrations of fatty acids and their metabolites varied between LPS-challenged mice on HFD or CD, respectively. To investigate whether systemic metabolic changes were sustained long-term, mice fed HFD were shifted back to CD after four weeks (HFD > CD). When shifted back to CD, serum metabolites returned to baseline levels, and so did the response to LPS. Our results imply that systemic metabolism rapidly adapts to dietary changes. The profound systemic metabolic rewiring observed in response to diet might affect immune cell reprogramming and inflammatory responses.

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Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer

Cited by 79 publications

References 50 publications

Current Methods of Magnetic Resonance for Noninvasive Assessment of Molecular Aspects of Pathoetiology in Multiple Sclerosis

Current Methods of Magnetic Resonance for Noninvasive Assessment of Molecular Aspects of Pathoetiology in Multiple Sclerosis

Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer

Metabolomic Profiling Reveals Distinct and Mutual Effects of Diet and Inflammation in Shaping Systemic Metabolism in Ldlr−/− Mice

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