Cancer-specific production of n-acetylaspartate via nat8l overexpression in non-small cell lung cancer and its potential as a circulating biomarker

Tzu Fang Lou, Deepa Sethuraman, Patrick Dospoy, Pallevi Srivastva, Hyun Seok Kim, Joongsoo Kim, Xiaotu Ma, Pei Hsuan Chen, Kenneth E. Huffman, Robin E. Frink, Jill E. Larsen, Cheryl Lewis, Sang Won Um, Duk Hwan Kim, Jung Mo Ahn, Ralph J. DeBerardinis, Michael A. White, John D. Minna, Hyuntae Yoo

Research output: Contribution to journalArticle

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Abstract

In order to identify new cancer-associated metabolites that may be useful for early detection of lung cancer, we performed a global metabolite profiling of a non-small cell lung cancer (NSCLC) line and immortalized normal lung epithelial cells from the same patient. Among several metabolites with significant cancer/normal differences, we identified a unique metabolic compound, N-acetylaspartate (NAA), in cancer cells- undetectable in normal lung epithelium. NAA's cancer-specific detection was validated in additional cancer and control lung cells as well as selected NSCLC patient tumors and control tissues. NAA's cancer specificity was further supported in our analysis of NAA synthetase (gene symbol: NAT8L) gene expression levels in The Cancer Genome Atlas: elevated NAT8L expression in approximately 40% of adenocarcinoma and squamous cell carcinoma cases (N = 577), with minimal expression in all nonmalignant lung tissues (N = 74). We then showed that NAT8L is functionally involved in NAA production of NSCLC cells through siRNA-mediated suppression of NAT8L, which caused selective reduction of intracellular and secreted NAA. Our cell culture experiments also indicated that NAA biosynthesis in NSCLC cells depends on glutamine availability. For preliminary evaluation of NAA's clinical potential as a circulating biomarker, we developed a sensitive NAA blood assay and found that NAA blood levels were elevated in 46% of NSCLC patients (N = 13) in comparison with age-matched healthy controls (N = 21) among individuals aged 55 years or younger. Taken together, these results indicate that NAA is produced specifically in NSCLC tumors through NAT8L overexpression, and its extracellular secretion can be detected in blood.

Original languageEnglish (US)
Pages (from-to)43-52
Number of pages10
JournalCancer Prevention Research
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2016

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Non-Small Cell Lung Carcinoma
Biomarkers
Neoplasms
Lung
Lung Neoplasms
N-acetylaspartate
Atlases
Ligases
Glutamine
Early Detection of Cancer
Small Interfering RNA
Squamous Cell Carcinoma
Adenocarcinoma
Epithelium
Cell Culture Techniques
Epithelial Cells
Genome
Gene Expression
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cancer-specific production of n-acetylaspartate via nat8l overexpression in non-small cell lung cancer and its potential as a circulating biomarker. / Lou, Tzu Fang; Sethuraman, Deepa; Dospoy, Patrick; Srivastva, Pallevi; Kim, Hyun Seok; Kim, Joongsoo; Ma, Xiaotu; Chen, Pei Hsuan; Huffman, Kenneth E.; Frink, Robin E.; Larsen, Jill E.; Lewis, Cheryl; Um, Sang Won; Kim, Duk Hwan; Ahn, Jung Mo; DeBerardinis, Ralph J.; White, Michael A.; Minna, John D.; Yoo, Hyuntae.

In: Cancer Prevention Research, Vol. 9, No. 1, 01.01.2016, p. 43-52.

Research output: Contribution to journalArticle

Lou, Tzu Fang ; Sethuraman, Deepa ; Dospoy, Patrick ; Srivastva, Pallevi ; Kim, Hyun Seok ; Kim, Joongsoo ; Ma, Xiaotu ; Chen, Pei Hsuan ; Huffman, Kenneth E. ; Frink, Robin E. ; Larsen, Jill E. ; Lewis, Cheryl ; Um, Sang Won ; Kim, Duk Hwan ; Ahn, Jung Mo ; DeBerardinis, Ralph J. ; White, Michael A. ; Minna, John D. ; Yoo, Hyuntae. / Cancer-specific production of n-acetylaspartate via nat8l overexpression in non-small cell lung cancer and its potential as a circulating biomarker. In: Cancer Prevention Research. 2016 ; Vol. 9, No. 1. pp. 43-52.
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AU - Srivastva, Pallevi

AU - Kim, Hyun Seok

AU - Kim, Joongsoo

AU - Ma, Xiaotu

AU - Chen, Pei Hsuan

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AU - Frink, Robin E.

AU - Larsen, Jill E.

AU - Lewis, Cheryl

AU - Um, Sang Won

AU - Kim, Duk Hwan

AU - Ahn, Jung Mo

AU - DeBerardinis, Ralph J.

AU - White, Michael A.

AU - Minna, John D.

AU - Yoo, Hyuntae

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