Skip to main content
Journal cover image

Role of Increased n-acetylaspartate Levels in Cancer.

Publication ,  Journal Article
Zand, B; Previs, RA; Zacharias, NM; Rupaimoole, R; Mitamura, T; Nagaraja, AS; Guindani, M; Dalton, HJ; Yang, L; Baddour, J; Achreja, A; Hu, W ...
Published in: J Natl Cancer Inst
January 26, 2016

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).

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Natl Cancer Inst

DOI

EISSN

1460-2105

Publication Date

January 26, 2016

Volume

108

Issue

6

Start / End Page

djv426

Location

United States

Related Subject Headings

  • Tandem Mass Spectrometry
  • Ovary
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Grading
  • Mice
  • Kaplan-Meier Estimate
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Gene Expression Regulation, Enzymologic
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Zand, B., Previs, R. A., Zacharias, N. M., Rupaimoole, R., Mitamura, T., Nagaraja, A. S., … Sood, A. K. (2016). Role of Increased n-acetylaspartate Levels in Cancer. J Natl Cancer Inst, 108(6), djv426. https://doi.org/10.1093/jnci/djv426
Zand, Behrouz, Rebecca A. Previs, Niki M. Zacharias, Rajesha Rupaimoole, Takashi Mitamura, Archana Sidalaghatta Nagaraja, Michele Guindani, et al. “Role of Increased n-acetylaspartate Levels in Cancer.J Natl Cancer Inst 108, no. 6 (January 26, 2016): djv426. https://doi.org/10.1093/jnci/djv426.
Zand B, Previs RA, Zacharias NM, Rupaimoole R, Mitamura T, Nagaraja AS, et al. Role of Increased n-acetylaspartate Levels in Cancer. J Natl Cancer Inst. 2016 Jan 26;108(6):djv426.
Zand, Behrouz, et al. “Role of Increased n-acetylaspartate Levels in Cancer.J Natl Cancer Inst, vol. 108, no. 6, Jan. 2016, p. djv426. Pubmed, doi:10.1093/jnci/djv426.
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 AK. Role of Increased n-acetylaspartate Levels in Cancer. J Natl Cancer Inst. 2016 Jan 26;108(6):djv426.
Journal cover image

Published In

J Natl Cancer Inst

DOI

EISSN

1460-2105

Publication Date

January 26, 2016

Volume

108

Issue

6

Start / End Page

djv426

Location

United States

Related Subject Headings

  • Tandem Mass Spectrometry
  • Ovary
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Grading
  • Mice
  • Kaplan-Meier Estimate
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Gene Expression Regulation, Enzymologic