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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
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Multidisciplinary Digital Publishing Institute
2023
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| Online Access: | https://hdl.handle.net/1721.1/152540 |
| _version_ | 1811087046397132800 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering 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 |
| author_sort | Zhang, Jie |
| collection | MIT |
| 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. |
| first_indexed | 2024-09-23T13:38:56Z |
| format | Article |
| id | mit-1721.1/152540 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:38:56Z |
| publishDate | 2023 |
| publisher | Multidisciplinary Digital Publishing Institute |
| record_format | dspace |
| spelling | mit-1721.1/1525402024-01-22T21:48:14Z Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells 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 Massachusetts Institute of Technology. Department of Chemical Engineering 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. 2023-10-27T19:58:59Z 2023-10-27T19:58:59Z 2023-10-19 2023-10-27T10:27:15Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/152540 Biomedicines 11 (10): 2842 (2023) PUBLISHER_CC http://dx.doi.org/10.3390/biomedicines11102842 Creative Commons Attribution https://creativecommons.org/licenses/by/4.0/ application/pdf Multidisciplinary Digital Publishing Institute Multidisciplinary Digital Publishing Institute |
| spellingShingle | 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 Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells |
| 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 |
| url | https://hdl.handle.net/1721.1/152540 |
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