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

Author:

Zhang Jie123,Keibler Mark A.14,Dong Wentao15ORCID,Ghelfi Jenny2,Cordes Thekla26,Kanashova Tamara7,Pailot Arnaud2,Linster Carole L.2ORCID,Dittmar Gunnar78ORCID,Metallo Christian M.19,Lautenschlaeger Tim1011,Hiller Karsten26,Stephanopoulos Gregory1

Affiliation:

1. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

2. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367 Belvaux, Luxembourg

3. Biomia Aps, Kemitorvet 220, 2800 Kongens Lyngby, Denmark

4. Alnylam Pharmaceuticals, Cambridge, MA 02139, USA

5. Department of Chemical Engineering, Department of Genetics, Institute for Chemistry, Engineering & Medicine for Human Health, Stanford University, Stanford, CA 94305, USA

6. Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, 38106 Braunschweig, Germany

7. Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany

8. Luxembourg Institute of Health, L-1445 Strassen, Luxembourg

9. Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA

10. Department of Radiation Oncology, Wexner Medical Center, Ohio State University, Columbus, OH 43221, USA

11. Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

Abstract

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.

Funder

NIH

Fonds National de la Recherche, Luxembourg

Publisher

MDPI AG

Subject

General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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