Role of Increased n-acetylaspartate Levels in Cancer. J Natl Cancer Inst 2016 Jan 26;108(6):djv426
Date
01/29/2016Pubmed ID
26819345Pubmed Central ID
PMC4849357DOI
10.1093/jnci/djv426Scopus ID
2-s2.0-84977070436 (requires institutional sign-in at Scopus site) 46 CitationsAbstract
BACKGROUND: The clinical and biological effects of metabolic alterations in cancer are not fully understood.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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).
Author List
Zand B, Previs RA, Zacharias NM, Rupaimoole R, Mitamura T, Nagaraja AS, Guindani M, Dalton HJ, Yang L, Baddour J, Achreja A, Hu W, Pecot CV, Ivan C, Wu SY, McCullough CR, Gharpure KM, Shoshan E, Pradeep S, Mangala LS, Rodriguez-Aguayo C, Wang Y, Nick AM, Davies MA, Armaiz-Pena G, Liu J, Lutgendorf SK, Baggerly KA, Eli MB, Lopez-Berestein G, Nagrath D, Bhattacharya PK, Sood AKAuthor
Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AcetyltransferasesAnimals
Apoptosis
Aspartic Acid
Biomarkers, Tumor
Cell Line, Tumor
Cell Proliferation
Cell Survival
Chromatography, High Pressure Liquid
Cystadenocarcinoma, Serous
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
Kaplan-Meier Estimate
Mice
Neoplasm Grading
Ovarian Neoplasms
Ovary
Tandem Mass Spectrometry
