aldehyde dehydrogenase 1A1 (ALDH1A1); cancer metabolism; erythronate; pentose phosphate pathway; untargeted metabolomics; Medicine (miscellaneous); Biochemistry, Genetics and Molecular Biology (all); General Biochemistry, Genetics and Molecular Biology
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
ZHANG, Jie ; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA ; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367 Belvaux, Luxembourg ; Biomia Aps, Kemitorvet 220, 2800 Kongens Lyngby, Denmark
Keibler, Mark A; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA ; Alnylam Pharmaceuticals, Cambridge, MA 02139, USA
Dong, Wentao ; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA ; Department of Chemical Engineering, Department of Genetics, Institute for Chemistry, Engineering & Medicine for Human Health, Stanford University, Stanford, CA 94305, USA
GHELFI, Jenny ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
Cordes, Thekla; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367 Belvaux, Luxembourg ; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, 38106 Braunschweig, Germany
Kanashova, Tamara; Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany
Pailot, Arnaud; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367 Belvaux, Luxembourg
LINSTER, Carole ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Enzymology and Metabolism
DITTMAR, Gunnar ; University of Luxembourg ; Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany ; Luxembourg Institute of Health, L-1445 Strassen, Luxembourg
Metallo, Christian M; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA ; Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Lautenschlaeger, Tim; Department of Radiation Oncology, Wexner Medical Center, Ohio State University, Columbus, OH 43221, USA ; Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
HILLER, Karsten ; University of Luxembourg ; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, 38106 Braunschweig, Germany
Stephanopoulos, Gregory; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Research on cancer metabolism in Stephanopoulos Lab is funded by NIH grants 1R01DK075850-01 and 1R01CA160458-01A1 (USA). J.Z. is supported by a fellowship from LCSB (Luxembourg). This study was supported by the Fonds National de la Recherche, Luxembourg (ATTRACT A10/03).
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