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Role of Increased n-acetylaspartate Levels in Cancer
Journal article   Open access   Peer reviewed

Role of Increased n-acetylaspartate Levels in Cancer

Behrouz Zand, Rebecca A Previs, Niki M Zacharias, Rajesha Rupaimoole, Takashi Mitamura, Archana Sidalaghatta Nagaraja, Michele Guindani, Heather J Dalton, Lifeng Yang, Joelle Baddour, …
JNCI : Journal of the National Cancer Institute, Vol.108(6), pp.djv426-djv426
01/26/2016
DOI: 10.1093/jnci/djv426
PMCID: PMC4849357
PMID: 26819345
url
https://doi.org/10.1093/jnci/djv426View
Published (Version of record) Open Access

Abstract

The clinical and biological effects of metabolic alterations in cancer are not fully understood. In high-grade serous ovarian cancer (HGSOC) samples (n = 101), over 170 metabolites were profiled and compared with normal ovarian tissues (n = 15). To determine NAT8L gene expression across different cancer types, we analyzed the RNA expression of cancer types using RNASeqV2 data available from the open access The Cancer Genome Atlas (TCGA) website (http://www.cbioportal.org/public-portal/). Using NAT8L siRNA, molecular techniques and histological analysis, we determined cancer cell viability, proliferation, apoptosis, and tumor growth in in vitro and in vivo (n = 6-10 mice/group) settings. Data were analyzed with the Student's t test and Kaplan-Meier analysis. Statistical tests were two-sided. Patients with high levels of tumoral NAA and its biosynthetic enzyme, aspartate N-acetyltransferase (NAT8L), had worse overall survival than patients with low levels of NAA and NAT8L. The overall survival duration of patients with higher-than-median NAA levels (3.6 years) was lower than that of patients with lower-than-median NAA levels (5.1 years, P = .03). High NAT8L gene expression in other cancers (melanoma, renal cell, breast, colon, and uterine cancers) was associated with worse overall survival. NAT8L silencing reduced cancer cell viability (HEYA8: control siRNA 90.61% ± 2.53, NAT8L siRNA 39.43% ± 3.00, P < .001; A2780: control siRNA 90.59% ± 2.53, NAT8L siRNA 7.44% ± 1.71, P < .001) and proliferation (HEYA8: control siRNA 74.83% ± 0.92, NAT8L siRNA 55.70% ± 1.54, P < .001; A2780: control siRNA 50.17% ± 4.13, NAT8L siRNA 26.52% ± 3.70, P < .001), which was rescued by addition of NAA. In orthotopic mouse models (ovarian cancer and melanoma), NAT8L silencing reduced tumor growth statistically significantly (A2780: control siRNA 0.52 g ± 0.15, NAT8L siRNA 0.08 g ± 0.17, P < .001; HEYA8: control siRNA 0.79 g ± 0.42, NAT8L siRNA 0.24 g ± 0.18, P = .008, A375-SM: control siRNA 0.55 g ± 0.22, NAT8L siRNA 0.21 g ± 0.17 g, P = .001). NAT8L silencing downregulated the anti-apoptotic pathway, which was mediated through FOXM1. These findings indicate that the NAA pathway has a prominent role in promoting tumor growth and represents a valuable target for anticancer therapy.Altered energy metabolism is a hallmark of cancer (1). Proliferating cancer cells have much greater metabolic requirements than nonproliferating differentiated cells (2,3). Moreover, altered cancer metabolism elevates unique metabolic intermediates, which can promote cancer survival and progression (4,5). Furthermore, emerging evidence suggests that proliferating cancer cells exploit alternative metabolic pathways to meet their high demand for energy and to accumulate biomass (6-8).
 Apoptosis Acetyltransferases - metabolism Cell Proliferation Cell Survival Humans Cystadenocarcinoma, Serous - metabolism Gene Expression Regulation, Neoplastic Kaplan-Meier Estimate Ovarian Neoplasms - pathology Chromatography, High Pressure Liquid Cystadenocarcinoma, Serous - pathology Gene Expression Regulation, Enzymologic Tandem Mass Spectrometry Animals Neoplasm Grading Biomarkers, Tumor - metabolism Cell Line, Tumor Aspartic Acid - metabolism Female Mice Ovarian Neoplasms - metabolism Aspartic Acid - analogs & derivatives Ovary - metabolism

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