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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2023-10-01
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| Online Access: | https://www.mdpi.com/2227-9059/11/10/2842 |
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| author | Jie Zhang Mark A. Keibler Wentao Dong Jenny Ghelfi Thekla Cordes Tamara Kanashova Arnaud Pailot Carole L. Linster Gunnar Dittmar Christian M. Metallo Tim Lautenschlaeger Karsten Hiller Gregory Stephanopoulos |
| author_facet | Jie Zhang Mark A. Keibler Wentao Dong Jenny Ghelfi Thekla Cordes Tamara Kanashova Arnaud Pailot Carole L. Linster Gunnar Dittmar Christian M. Metallo Tim Lautenschlaeger Karsten Hiller Gregory Stephanopoulos |
| author_sort | Jie Zhang |
| collection | DOAJ |
| description | 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. |
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| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T21:24:31Z |
| publishDate | 2023-10-01 |
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| series | Biomedicines |
| spelling | doaj.art-6f2c58a8ebee4bb3b1b7360e66bf89902023-11-19T15:47:53ZengMDPI AGBiomedicines2227-90592023-10-011110284210.3390/biomedicines11102842Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer CellsJie Zhang0Mark A. Keibler1Wentao Dong2Jenny Ghelfi3Thekla Cordes4Tamara Kanashova5Arnaud Pailot6Carole L. Linster7Gunnar Dittmar8Christian M. Metallo9Tim Lautenschlaeger10Karsten Hiller11Gregory Stephanopoulos12Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USADepartment of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USADepartment of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USALuxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367 Belvaux, LuxembourgLuxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367 Belvaux, LuxembourgMax-Delbrück Center for Molecular Medicine, 13125 Berlin, GermanyLuxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367 Belvaux, LuxembourgLuxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367 Belvaux, LuxembourgMax-Delbrück Center for Molecular Medicine, 13125 Berlin, GermanyDepartment of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USADepartment of Radiation Oncology, Wexner Medical Center, Ohio State University, Columbus, OH 43221, USALuxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367 Belvaux, LuxembourgDepartment of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USAUsing 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.https://www.mdpi.com/2227-9059/11/10/2842cancer metabolismuntargeted metabolomicserythronatepentose phosphate pathwayaldehyde dehydrogenase 1A1 (ALDH1A1) |
| spellingShingle | Jie Zhang Mark A. Keibler Wentao Dong Jenny Ghelfi Thekla Cordes Tamara Kanashova Arnaud Pailot Carole L. Linster Gunnar Dittmar Christian M. Metallo Tim Lautenschlaeger Karsten Hiller Gregory Stephanopoulos Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells Biomedicines cancer metabolism untargeted metabolomics erythronate pentose phosphate pathway aldehyde dehydrogenase 1A1 (ALDH1A1) |
| title | Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells |
| title_full | Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells |
| title_fullStr | Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells |
| title_full_unstemmed | Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells |
| title_short | Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells |
| title_sort | stable isotope assisted untargeted metabolomics identifies aldh1a1 driven erythronate accumulation in lung cancer cells |
| topic | cancer metabolism untargeted metabolomics erythronate pentose phosphate pathway aldehyde dehydrogenase 1A1 (ALDH1A1) |
| url | https://www.mdpi.com/2227-9059/11/10/2842 |
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