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

dc.contributor.authorZhang, Jie
dc.contributor.authorKeibler, Mark A.
dc.contributor.authorDong, Wentao
dc.contributor.authorGhelfi, Jenny
dc.contributor.authorCordes, Thekla
dc.contributor.authorKanashova, Tamara
dc.contributor.authorPailot, Arnaud
dc.contributor.authorLinster, Carole L.
dc.contributor.authorDittmar, Gunnar
dc.contributor.authorMetallo, Christian M.
dc.contributor.authorLautenschlaeger, Tim
dc.contributor.authorHiller, Karsten
dc.contributor.authorStephanopoulos, Gregory
dc.contributor.departmentRadiation Oncology, School of Medicine
dc.date.accessioned2024-03-22T14:55:43Z
dc.date.available2024-03-22T14:55:43Z
dc.date.issued2023-10-19
dc.description.abstractUsing 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.
dc.eprint.versionFinal published version
dc.identifier.citationZhang J, Keibler MA, Dong W, et al. Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells. Biomedicines. 2023;11(10):2842. Published 2023 Oct 19. doi:10.3390/biomedicines11102842
dc.identifier.urihttps://hdl.handle.net/1805/39446
dc.language.isoen_US
dc.publisherMDPI
dc.relation.isversionof10.3390/biomedicines11102842
dc.relation.journalBiomedicines
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcePMC
dc.subjectCancer metabolism
dc.subjectUntargeted metabolomics
dc.subjectErythronate
dc.subjectPentose phosphate pathway
dc.subjectAldehyde dehydrogenase 1A1 (ALDH1A1)
dc.titleStable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells
dc.typeArticle
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