Abstract 3481: Dietary acetate supplementation as a means of inducing glioma stem cell growth arrest

Abstract

Abstract Glioma, the most common primary brain tumor of the adult central nervous system, is associated with a poor prognosis due, in part, to the presence of chemoradiotherapy-resistant glioma stem-like cells responsible for inevitable post-surgical recurrence. N-acetyl-L-aspartate (NAA), one of the most concentrated metabolic sources of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA degradation, are significantly reduced in glioma tumors. NAA-derived acetate is converted to acetyl coenzyme A via acetyl-CoA synthetase (AceCS) for use in lipogenesis, protein/histone acetylation, and the TCA cycle. We propose that glyceryltriacetate (GTA), a FDA approved food additive with “generally regarded as safe” status, may be an effective means of reducing glioma growth via restoration of acetate levels. The effect of GTA on the growth of both established (Hs683, HOG) and stem-like (grade II OG33, grade III OG35) oligodendroglioma cell lines was assessed. In vitro, GTA induced growth arrest in all cells examined (i.e., increased proportion of cells in G0/G1 and reduced S phase cells by flow cytometry of propidium iodide labeled cells 24 hours after treatment and unbiased trypan blue exclusion based cytometry up to 5 days post-treatment). Growth arrest was not associated with apoptosis (lack of cleaved poly ADP-ribose polymerase immunolabeling), but differentiation (increased CNPase expression). ASPA expression was greater in stem-like cells when grown in stem cell media than differentiation media and was decreased in GTA-treated OG35 cells. Interestingly, GTA did not decrease ASPA expression in OG33 cells, but induced a novel 26 kDa ASPA isoform. ASPA and AceCS1 were co-localized within the nucleus. Nuclear, but not cytosolic, ASPA expression was decreased upon GTA addition in stem cell media, but not differentiation media. Finally, the effect of GTA on orthotopically grafted luciferase expressing OG33 and OG35 cells was assessed. Bioluminescence and tumor volume were reduced in GTA treated mice. These data suggest that the nuclear ASPA/AceCS1 co-localization provides acetate for histone acetylation to maintain cells in a progenitor/stem-like state and that decreased ASPA promotes gliomagenesis. Inasmuch as infants with Canavan Disease, a leukodystrophy due to ASPA mutation, treated with high dose GTA showed no significant side effects, GTA may prove an effective therapy to prevent recurrence by inducing growth arrest/differentiation of glioma stem-like cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3481. doi:1538-7445.AM2012-3481