Abstract 3663: Characterization of aspartoacylase in oligodendroglioma
Authors: Long Patrick M. 
Published: June 2012

Aspartoacylase (ASPA, ACY2) is an oligodendrocyte-derived amino acid deacetylase (aminoacylase) responsible for supplying acetate for myelin lipid synthesis via the cleavage of N-acetyl-L-aspartate (NAA) into free acetate and aspartate. Our unpublished observations showed ASPA to be significantly down-regulated at the transcriptional and translational level in high-grade oligodendroglioma tumor samples relative to normal brain tissue. Additionally, in silico data indicates that low ASPA expression in oligodendroglioma correlates with increased mortality. While aminoacylase 1 (ACY1) serves as a putative tumor suppressor in small cell lung and renal cell carcinoma, the role of ASPA in oligodendroglioma is previously unexplored. We therefore endeavored to characterize the expression of ASPA in two oligodendroglioma cell lines, Hs683 and HOG cells, and in a murine oligodendrocyte precursor cell line immortalized via stable transfection with the constitutively active ErbB2 receptor (Oli-neu cells). In contrast to our in vivo data, Oli-neu cells displayed lower ASPA expression relative to Hs683 and HOG cells. Nonetheless, ASPA expression increased with time in culture. Unlike Hs683 and HOG cells, which were recalcitrant to differentiation, Oli-neu cells were responsive to cAMP-induced differentiation, as revealed by CNPase up-regulation and a concordant increase in ASPA expression. Interestingly, treatment with ASPA's only known substrate, NAA, significantly inhibited the temporal increase in both CNPase and ASPA expression within Oli-neu cells. Conversely, NAA treatment had no effect on CNPase or ASPA expression in either Hs683 or HOG cells. To address whether the cAMP-mediated ASPA up-regulation in Oli-neu cells was related to differentiation or activation of cAMP signal transduction, Oli-neu cells were treated with an ErbB2 antagonist. In contrast to cAMP, ErbB2-mediated differentiation was associated with down-regulation of ASPA expression. Immunocytochemically, ASPA appears to be diffusely distributed throughout the cytosol in Oli-neu cells. Although ASPA has been previous characterized as a predominantly cytosolic/nuclear protein, in Hs683 and HOG cells ASPA exhibits a highly punctate membrane-associated pattern of expression. Collectively, our results reveal distinct patterns of ASPA regulation and subcellular localization in two oligodendroglioma cell lines compared to a representative oligodendrocyte precursor cell line. More importantly, we reveal distinct in vitro and in vivo ASPA regulation in oligodendroglioma, thus suggesting a possible role of the tumor microenvironment in regulating ASPA expression.

This work was supported by a LCCRO/VCC Pilot Project grant, a UVM Internal Grants Program Pilot Project Award, and NIH/NCRR R01NS045225 (DMJ), Neuroscience COBRE (NIH NCRR P20 RR016435), and P30 CA22435 support of the VCC DNA Analysis facility.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3663. doi:10.1158/1538-7445.AM2011-3663