Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells

Using an untargeted stable isotope-assisted metabolomics approach, we identify erythronate as a metabolite that accumulates in several human cancer cell lines. Erythronate has been reported to be a detoxification product derived from off-target glycolytic metabolism. We use chemical inhibitors and g...

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Bibliographic Details
Published in:Biomedicines 2023-10, Vol.11 (10), p.2842
Main Authors: Zhang, Jie, Keibler, Mark A, Dong, Wentao, Ghelfi, Jenny, Cordes, Thekla, Kanashova, Tamara, Pailot, Arnaud, Linster, Carole L, Dittmar, Gunnar, Metallo, Christian M, Lautenschlaeger, Tim, Hiller, Karsten, Stephanopoulos, Gregory
Format: Article
Language:English
Subjects:
Aldehyde dehydrogenase
aldehyde dehydrogenase 1A1 (ALDH1A1)
Aldehydes
Biomarkers
Biosynthesis
Cancer
Cancer cells
cancer metabolism
Cells
Chemical inhibitors
Chromatography
Dehydrogenases
Dephosphorylation
Detoxification
Enzymes
erythronate
Genetic engineering
Glucose
Glycolysis
Labeling
Lung cancer
Mass spectrometry
Medical research
Medicine, Experimental
Metabolism
Metabolites
Metabolomics
Monosaccharides
Oxidation
Pentose phosphate pathway
Phosphatase
Phosphates
Physiological aspects
Prostate
Proteins
Proteomics
Scientific imaging
Sugars
Tumor cell lines
Tumors
untargeted metabolomics
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Summary:Using an untargeted stable isotope-assisted metabolomics approach, we identify erythronate as a metabolite that accumulates in several human cancer cell lines. Erythronate has been reported to be a detoxification product derived from off-target glycolytic metabolism. We use chemical inhibitors and genetic silencing to define the pentose phosphate pathway intermediate erythrose 4-phosphate (E4P) as the starting substrate for erythronate production. However, following enzyme assay-coupled protein fractionation and subsequent proteomics analysis, we identify aldehyde dehydrogenase 1A1 (ALDH1A1) as the predominant contributor to erythrose oxidation to erythronate in cell extracts. Through modulating ALDH1A1 expression in cancer cell lines, we provide additional support. We hence describe a possible alternative route to erythronate production involving the dephosphorylation of E4P to form erythrose, followed by its oxidation by ALDH1A1. Finally, we measure increased erythronate concentrations in tumors relative to adjacent normal tissues from lung cancer patients. These findings suggest the accumulation of erythronate to be an example of metabolic reprogramming in cancer cells, raising the possibility that elevated levels of erythronate may serve as a biomarker of certain types of cancer.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines11102842