title: 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.affiliation: From the Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont 05405.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Long
authors.affiliation: the Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, and.
authors.forename: John R
authors.initials: JR
authors.lastname: Moffett
authors.affiliation: the Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, and.
authors.forename: Aryan M A
authors.initials: AMA
authors.lastname: Namboodiri
authors.affiliation: the Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts 02215.
authors.forename: Mariano S
authors.initials: MS
authors.lastname: Viapiano
authors.affiliation: the Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts 02215.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Lawler
authors.affiliation: From the Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont 05405,. Electronic address: diane.jaworski@uvm.edu.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Jaworski
mesh_terms: D000581:Amidohydrolases / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009837:Oligodendroglioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D004151:Dipeptides; D009363:Neoplasm Proteins; D018696:Neuroprotective Agents; C027172:isospaglumic acid; D001224:Aspartic Acid; C000179:N-acetylaspartate; D000581:Amidohydrolases; C019751:aspartoacylase
keywords: Cancer Stem Cells; Differentiation; Metabolism; Oligodendrocytes; Proliferation