N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) promote growth and inhibit differentiation of glioma stem-like cells.

Abstract

Metabolic reprogramming is a pathological feature of cancer and a driver of tumor cell transformation. N-Acetylaspartate (NAA) is one of the most abundant amino acid derivatives in the brain and serves as a source of metabolic acetate for oligodendrocyte myelination and protein/histone acetylation or a precursor for the synthesis of the neurotransmitter N-acetylaspartylglutamate (NAAG). NAA and NAAG as well as aspartoacylase (ASPA), the enzyme responsible for NAA degradation, are significantly reduced in glioma tumors, suggesting a possible role for decreased acetate metabolism in tumorigenesis. This study sought to examine the effects of NAA and NAAG on primary tumor-derived glioma stem-like cells (GSCs) from oligodendroglioma as well as proneural and mesenchymal glioblastoma, relative to oligodendrocyte progenitor cells (Oli-Neu). Although the NAA dicarboxylate transporter NaDC3 is primarily thought to be expressed by astrocytes, all cell lines expressed NaDC3 and, thus, are capable of NAA up-take. Treatment with NAA or NAAG significantly increased GSC growth and suppressed differentiation of Oli-Neu cells and proneural GSCs. Interestingly, ASPA was expressed in both the cytosol and nuclei of GSCs and exhibited greatest nuclear immunoreactivity in differentiation-resistant GSCs. Both NAA and NAAG elicited the expression of a novel immunoreactive ASPA species in select GSC nuclei, suggesting differential ASPA regulation in response to these metabolites. Therefore, this study highlights a potential role for nuclear ASPA expression in GSC malignancy and suggests that the use of NAA or NAAG is not an appropriate therapeutic approach to increase acetate bioavailability in glioma. Thus, an alternative acetate source is required.

• Authors: Patrick M Long, John R Moffett, Aryan M A Namboodiri, Mariano S Viapiano, Sean E Lawler, Diane M Jaworski
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 36 Pg. 26188-26200 (Sep 06 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23884408 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Dipeptides
• Neoplasm Proteins
• Neuroprotective Agents
• isospaglumic acid
• Aspartic Acid
• N-acetylaspartate
• Amidohydrolases
• aspartoacylase

Topics

• Amidohydrolases (biosynthesis, genetics)
• Animals
• Aspartic Acid (analogs & derivatives, pharmacology)
• Cell Differentiation (drug effects)
• Cell Line, Transformed
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dipeptides (pharmacology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Neoplasm Proteins (biosynthesis, genetics)
• Neoplastic Stem Cells (metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Oligodendroglioma (drug therapy, genetics, metabolism, pathology)