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Cancer Sci. 2019 Dec 11. doi: 10.1111/cas.14278. [Epub ahead of print]

Impacts of NRF2 activation in non-small-cell lung cancer cell lines on extracellular metabolites.

Author information

1
Department of Integrative Genomics, Tohoku University Tohoku Medical Megabank Organization, Sendai, Japan.
2
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
3
Department of System Bioinformatics, Tohoku University Graduate School of Information Sciences, Sendai, Japan.
4
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
5
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
6
Astellas Pharma Inc., Tokyo, Japan.

Abstract

Aberrant activation of NRF2 is as a critical prognostic factor that drives the malignant progression of various cancers. Cancer cells with persistent NRF2 activation heavily rely on NRF2 activity for therapeutic resistance and aggressive tumorigenic capacity. To clarify the metabolic features of NRF2-activated lung cancers, we conducted targeted metabolomic (T-Met) and global metabolomic (G-Met) analyses of non-small-cell lung cancer (NSCLC) cell lines in combination with exome and transcriptome analyses. Exome analysis of 88 cell lines (49 adenocarcinoma, 14 large cell carcinoma, 15 squamous cell carcinoma and 10 others) identified non-synonymous mutations in the KEAP1, NRF2 and CUL3 genes. Judging from the elevated expression of NRF2 target genes, these mutations are expected to result in the constitutive stabilization of NRF2. Out of the 88 cell lines, 52 NSCLC cell lines (29 adenocarcinoma, 10 large cell carcinoma, 9 squamous cell carcinoma and 4 others) were subjected to T-Met analysis. Classification of the 52 cell lines into three groups according to the NRF2 target gene expression enabled us to draw typical metabolomic signatures induced by NRF2 activation. From the 52 cell lines, 18 NSCLC cell lines (14 adenocarcinoma, 2 large cell carcinoma, 1 squamous cell carcinoma and 1 others) were further chosen for G-Met and detailed transcriptome analyses. G-Met analysis of their culture supernatants revealed novel metabolites associated with NRF2 activity, which may be potential diagnostic biomarkers of NRF2 activation. This study also provides useful information for the exploration of new metabolic nodes for selective toxicity towards NRF2-activated NSCLC.

KEYWORDS:

NRF2; culture supernatant; metabolites; metabolome; non-small-cell lung cancer

PMID:
31828882
DOI:
10.1111/cas.14278
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