L-Glyceraldehyde Inhibits Neuroblastoma Cell Growth via a Multi-Modal Mechanism on Metabolism and Signaling

Author:

Forbes Martin12,Kempa Richard1,Mastrobuoni Guido1,Rayman Liam1,Pietzke Matthias13,Bayram Safak1,Arlt Birte124,Spruessel Annika4,Deubzer Hedwig E.24567ORCID,Kempa Stefan1ORCID

Affiliation:

1. Integrative Proteomics and Metabolomics, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str. 28, 10115 Berlin, Germany

2. Department of Pediatric Hematology and Oncology, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany

3. Mass Spectrometry Facility, MaxPlanck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany

4. Berliner Institut für Gesundheitsforschung (BIH), Anna-Louisa-Karsch-Strase 2, 10178 Berlin, Germany

5. German Cancer Consortium (DKTK), Partner Site Berlin, Invalidenstr. 80, 10115 Berlin, Germany

6. German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

7. Experimental and Clinical Research Center (ECRC), Charité and Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, 13125 Berlin, Germany

Abstract

Glyceraldehyde (GA) is a three-carbon monosaccharide that can be present in cells as a by-product of fructose metabolism. Bruno Mendel and Otto Warburg showed that the application of GA to cancer cells inhibits glycolysis and their growth. However, the molecular mechanism by which this occurred was not clarified. We describe a novel multi-modal mechanism by which the L-isomer of GA (L-GA) inhibits neuroblastoma cell growth. L-GA induces significant changes in the metabolic profile, promotes oxidative stress and hinders nucleotide biosynthesis. GC-MS and 13C-labeling was employed to measure the flow of carbon through glycolytic intermediates under L-GA treatment. It was found that L-GA is a potent inhibitor of glycolysis due to its proposed targeting of NAD(H)-dependent reactions. This results in growth inhibition, apoptosis and a redox crisis in neuroblastoma cells. It was confirmed that the redox mechanisms were modulated via L-GA by proteomic analysis. Analysis of nucleotide pools in L-GA-treated cells depicted a previously unreported observation, in which nucleotide biosynthesis is significantly inhibited. The inhibitory action of L-GA was partially relieved with the co-application of the antioxidant N-acetyl-cysteine. We present novel evidence for a simple sugar that inhibits cancer cell proliferation via dysregulating its fragile homeostatic environment.

Funder

TERMINATE-NB consortium

German Cancer Aid funding for the ENABLE consortium

Bundesministerium für Bildung und Forschung

Helmholtz Foundation

Sander foundation

Charité

MDC

Publisher

MDPI AG

Reference63 articles.

1. Krebszelle und Glycerinaldehyd;Mendel;Klin. Wochenschr.,1929

2. The metabolism of cancer cells;Warburg;Biochem. Z.,1924

3. Über Heilung von Mäuse-Ascites-Krebs durch D-und L-Glycerinaldehyd;Warburg;Z. Klin. Chem.,1963

4. The inhibition of glucolysis by glyceraldehyde;Stickland;Biochem. J.,1941

5. On the mechanism of the inhibition of glycolysis by glyceraldehyde;Needham;Biochem. J.,1951

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