N-Acetylaspartate (NAA) and N-Acetylaspartylglutamate (NAAG) Promote Growth and Inhibit Differentiation of Glioma Stem-like Cells

Long, Patrick M.; Moffett, John R.; Namboodiri, Aryan M.A.; Viapiano, Mariano S.; Lawler, Sean E.; Jaworski, Diane M.

doi:10.1074/jbc.m113.487553

Cited by 47 publications

(48 citation statements)

References 48 publications

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“…Although this might be explained by a high turnover of mitochondrial αKG, it raises the question of alternative substrates and/or compartmentalization effects. Acetate was recently shown to act as a bioenergetic substrate for glioblastoma (Mashimo et al , ), and NAA and NAAG supplemented to glioblastoma cells were found to support tumor growth (Long et al , ). NAA and NAAG are involved in the acetate metabolism which also regulates lipid synthesis and histone acetylation (Gao et al , ).…”

Section: Discussionmentioning

confidence: 99%

Altered metabolic landscape in IDH ‐mutant gliomas affects phospholipid, energy, and oxidative stress pathways

Fack

Tardito

Hochart³

et al. 2017

EMBO Mol Med

120

152

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Heterozygous mutations in NADP‐dependent isocitrate dehydrogenases (IDH) define the large majority of diffuse gliomas and are associated with hypermethylation of DNA and chromatin. The metabolic dysregulations imposed by these mutations, whether dependent or not on the oncometabolite D‐2‐hydroxyglutarate (D2HG), are less well understood. Here, we applied mass spectrometry imaging on intracranial patient‐derived xenografts of IDH‐mutant versus IDH wild‐type glioma to profile the distribution of metabolites at high anatomical resolution in situ. This approach was complemented by in vivo tracing of labeled nutrients followed by liquid chromatography–mass spectrometry (LC‐MS) analysis. Selected metabolites were verified on clinical specimen. Our data identify remarkable differences in the phospholipid composition of gliomas harboring the IDH1 mutation. Moreover, we show that these tumors are characterized by reduced glucose turnover and a lower energy potential, correlating with their reduced aggressivity. Despite these differences, our data also show that D2HG overproduction does not result in a global aberration of the central carbon metabolism, indicating strong adaptive mechanisms at hand. Intriguingly, D2HG shows no quantitatively important glucose‐derived label in IDH‐mutant tumors, which suggests that the synthesis of this oncometabolite may rely on alternative carbon sources. Despite a reduction in NADPH, glutathione levels are maintained. We found that genes coding for key enzymes in de novo glutathione synthesis are highly expressed in IDH‐mutant gliomas and the expression of cystathionine‐β‐synthase (CBS) correlates with patient survival in the oligodendroglial subtype. This study provides a detailed and clinically relevant insight into the in vivo metabolism of IDH1‐mutant gliomas and points to novel metabolic vulnerabilities in these tumors.

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Section: Discussionmentioning

confidence: 99%

Altered metabolic landscape in IDH ‐mutant gliomas affects phospholipid, energy, and oxidative stress pathways

Fack

Tardito

Hochart³

et al. 2017

EMBO Mol Med

120

152

View full text Add to dashboard Cite

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“…Increased RNA oxidation has been observed in post-mortem brains of subjects with mild cognitive impairment (47) and pre-symptomatic subjects with a familial AD mutation (10). Studies on AD revealed that neuronal RNA oxidation precedes the formation of amyloid β or tau pathology, the later are implicated in AD neurodegeneration (48). Increased RNA oxidation was also observed in the pre-symptomatic stage in transgenic mice expressing an ALS-linked mutant SOD1 G93A , suggesting that RNA oxidation is a common early event preceding motor neuron degeneration in ALS (13).…”

Section: Discussionmentioning

confidence: 99%

NAT8LmRNA oxidation is linked to neurodegeneration in multiple sclerosis

Kharel

Singhal

West

et al. 2020

Preprint

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RNA oxidation has been implicated in neurodegeneration, but the underlying mechanism for such effects is unclear. Recently, we demonstrated extensive RNA oxidation within the neurons in multiple sclerosis (MS) brain. In this report we identified selectively oxidized mRNAs in neuronal cells that pertained to neuropathological pathways. N-acetyl aspartate transferase 8 like (NAT8L) mRNA is one such transcript, whose translated product enzymatically synthesizes Nacetyl aspartic acid (NAA), a neuronal metabolite important for myelin synthesis. We reasoned that impediment of translation of an oxidized NAT8L mRNA will result in reduction in its cognate protein, thus lowering NAA level. This assertion is directly supported by our studies on a model cellular system, an MS animal model and postmortem human MS brain. Reduced NAA level in the brain hampers myelin integrity making neuronal axons more susceptible to damage, which contributes in MS neurodegeneration. Overall, this work provides a framework for mechanistic understanding of the link between RNA oxidation and neurodegenerative diseases.

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“…GTA significantly increased brain acetate [Mathew et al, ] and acetyl‐CoA levels [Soliman and Rosenberger, ], but did not increase NAA levels [Mathew et al, ]. That NAA levels are not increased is critical for the use of GTA as a cancer therapy since we showed that NAA accumulation promotes GSC proliferation [Long et al, ]. GTA also decreased plasma lactate and pyruvate concentrations and increased plasma ketone body concentration and resting energy [Bailey et al, ].…”

Section: Beneficial Effects Of Acetate—glyceryl Triacetate As a Cancementioning

confidence: 91%

“…Thus, similar to Canavan disease, glioma may be associated with reduced acetate bioavailability due to defective ASPA‐mediated NAA deacetylation. NAA supplementation is not a viable therapeutic approach since we demonstrated that treatment with physiological levels of NAA increased GSC proliferation in vitro [Long et al, ]. In contrast, GTA treatment induced in vitro cytostatic growth arrest of both oligodendroglioma GSCs [Long et al, ] and GBM GSCs [Long et al, ] with little to no effect on normal brain cells.…”

Section: Beneficial Effects Of Acetate—glyceryl Triacetate As a Cancementioning

confidence: 99%

Acetate as a Metabolic and Epigenetic Modifier of Cancer Therapy

2016

Self Cite

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Metabolic networks are significantly altered in neoplastic cells. This altered metabolic program leads to increased glycolysis and lipogenesis and decreased dependence on oxidative phosphorylation and oxygen consumption. Despite their limited mitochondrial respiration, cancer cells, nonetheless, derive sufficient energy from alternative carbon sources and metabolic pathways to maintain cell proliferation. They do so, in part, by utilizing fatty acids, amino acids, ketone bodies, and acetate, in addition to glucose. The alternative pathways used in the metabolism of these carbon sources provide opportunities for therapeutic manipulation. Acetate, in particular, has garnered increased attention in the context of cancer as both an epigenetic regulator of posttranslational protein modification, and as a carbon source for cancer cell biomass accumulation. However, to date, the data have not provided a clear understanding of the precise roles that protein acetylation and acetate oxidation play in carcinogenesis, cancer progression or treatment. This review highlights some of the major issues, discrepancies, and opportunities associated with the manipulation of acetate metabolism and acetylation-based signaling in cancer development and treatment.

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N-Acetylaspartate (NAA) and N-Acetylaspartylglutamate (NAAG) Promote Growth and Inhibit Differentiation of Glioma Stem-like Cells

Cited by 47 publications

References 48 publications

Altered metabolic landscape in IDH ‐mutant gliomas affects phospholipid, energy, and oxidative stress pathways

Altered metabolic landscape in IDH ‐mutant gliomas affects phospholipid, energy, and oxidative stress pathways

NAT8LmRNA oxidation is linked to neurodegeneration in multiple sclerosis

Acetate as a Metabolic and Epigenetic Modifier of Cancer Therapy

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