Differential aminoacylase expression in neuroblastoma

Department of Anatomy and Neurobiology, University of Vermont College of Medicine, Burlington, VT 05405, USA.
International Journal of Cancer (Impact Factor: 5.09). 09/2011; 129(6):1322-30. DOI: 10.1002/ijc.25798
Source: PubMed


Neuroblastoma, a cancer of the sympathetic nervous system, is the most common extracranial solid tumor in children. MYCN amplification and increased BDNF/TrkB signaling are features of high-risk tumors; yet, only ˜25% of malignant tumors display these features. Thus, the identification of additional biomarkers and therapeutic targets is essential. As aminoacylase 1 (ACY1), an amino acid deacetylase, is a putative tumor suppressor in small cell lung and renal cell carcinomas, we investigated whether it or the other family members aspartoacylase (ASPA, aminoacylase 2) or aminoacylase 3 (ACY3) could serve a similar function in neuroblastoma. Aminoacylase expression was examined in TrkB-positive, MYCN-amplified (SMS-KCNR and SK-N-BE) and TrkB-negative, non-MYCN-amplified (SK-N-AS, SK-N-SH, SH-SY5Y and SH-EP) neuroblastoma cell lines. Each aminoacylase exhibited distinct spatial localization (i.e., cytosolic ACY1, membrane-associated ASPA and nuclear ACY3). When SK-N-SH cells were treated with neural differentiation agents (e.g., retinoic acid and cAMP) in media containing 10% serum, ACY1 was the only aminoacylase whose expression was upregulated. ASPA was primarily expressed in SH-EP cells of a glial sublineage. ACY3 was more highly expressed in the TrkB-positive, MYCN-amplified lines. All three aminoacylases were expressed in normal human adrenal gland, a common site of neuroblastoma origin, but only ACY1 and ACY3 displayed detectable expression in primary neuroblastoma tumor. Bioinformatics data mining of Kaplan-Meier survival revealed that high ACY3 expression is correlated with poor prognosis, whereas low expression of ACY1 or ASPA is correlated with poor prognosis. These data suggest that aminoacylase expression is dysregulated in neuroblastoma.

Download full-text


Available from: Diane M Jaworski, Sep 19, 2014
  • Source
    • "AA3 expression in mouse brain has been verified by Northern blotting (Pushkin et al., 2004), although the precise neuroanatomical distribution has yet to be defined. Both proteins are expressed in primary neuroblastoma tumors (Long et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: 4-Hydroxy-2-nonenal (4HNE) and acrolein (ACR) are highly reactive neurotoxic products of lipid peroxidation that are implicated in the pathogenesis and progression of Alzheimer's and Parkinson's diseases. Conjugation with glutathione (GSH) initiates the 4HNE and ACR detoxification pathway, which generates the mercapturates of 4HNE and ACR that can be excreted. Prior work has shown that the efficiency of the GSH-dependent renal detoxification of haloalkene derived mercapturates is significantly decreased upon their deacetylation because of rapid transformation of the deacetylated products into toxic compounds mediated by β-lyase. The enzymes of the GSH-conjugation pathway and β-lyases are expressed in the brain, and we hypothesized that a similar toxicity mechanism may be initiated in the brain by the deacetylation of 4HNE- and ACR-mercapturate. The present study was performed to identify an enzyme(s) involved in 4HNE- and ACR-mercapturate deacetylation, characterize the brain expression of this enzyme and determine whether its inhibition decreases 4HNE and 4HNE-mercapturate neurotoxicity. We demonstrated that of two candidate deacetylases, aminoacylases 1 (AA1) and 3 (AA3), only AA3 efficiently deacetylates both 4HNE- and ACR-mercapturate. AA3 was further localized to neurons and blood vessels. Using a small molecule screen we generated high-affinity AA3 inhibitors. Two of them completely protected rat brain cortex neurons expressing AA3 from the toxicity of 4HNE-mercapturate. 4HNE-cysteine (4HNE-Cys) was also neurotoxic and its toxicity was mostly prevented by a β-lyase inhibitor, aminooxyacetate. The results suggest that the AA3 mediated deacetylation of 4HNE-mercapturate may be involved in the neurotoxicity of 4HNE.
    Toxicology and Applied Pharmacology 07/2012; 263(3):303-14. DOI:10.1016/j.taap.2012.07.002 · 3.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Proteome analysis has rapidly developed in the post-genome era and is now widely accepted as a complementary technology to genetic profiling. The improvement in the technology of both two-dimensional electrophoresis (2-DE) analysis as well as quantitative iTRAQ has made proteomics a valuable and powerful tool to study human diseases. Clinical bioinformatics, emerging science combining clinical informatics, bioinformatics, medical informatics, information technology, mathematics, and omics science together, can be considered to be one of critical elements addressing clinical relevant challenges in early diagnosis, efficient therapies, and predictive prognosis of patients with disease. A combination of proteome analysis with clinical bioinformatics has been developed as a promising experimental approach for the identification of diagnostic and prognostic markers and so on, suggesting that proteome-based analysis is a promising tool for the identification of prognostic and diagnostic markers as well as for novel therapeutic targets which could be used for the treatment of diseases. The integration of proteome-based approaches with data from genomic or genetic profiling will lead to a better understanding of different diseases, which will then contribute to the direct translation of the research findings into clinical practice.
    Bioinformatics of Human Proteomics, 01/2013: pages 1-15;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: High-risk neuroblastoma is an aggressive malignancy with high rates of treatment failure. We evaluated genetic variants associated with in vitro sensitivity to two derivatives of cyclophosphamide for association with clinical response in a separate replication cohort of neuroblastoma patients (n=2,709). Lymphoblastoid cell lines (LCLs) were exposed to increasing concentrations of 4-hydroperoxycyclophosphamide [4HC n=422] and phosphoramide mustard [PM n=428] to determine sensitivity. Genome-wide association studies (GWAS) were performed to identify single nucleotide polymorphisms (SNPs) associated with 4HC and PM sensitivity. SNPs consistently associated with LCL sensitivity were analyzed for associations with event-free survival in patients. Two linked SNPs, rs9908694 and rs1453560, were found to be associated with PM sensitivity in LCLs across populations and were associated with event-free survival in all patients (P=0.01) and within the high-risk subset (P=0.05). Our study highlights the value of cell-based models to identify candidate variants that may predict response to treatment in patients with cancer.Clinical Pharmacology & Therapeutics (2014); accepted article preview online 18 February 2014 doi:10.1038/clpt.2014.37.
    Clinical Pharmacology &#38 Therapeutics 02/2014; 95(6). DOI:10.1038/clpt.2014.37 · 7.90 Impact Factor
Show more