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

Simple Summary: Approximately half of all infants and children newly diagnosed with neuroblastoma are at high risk for relapse despite aggressive multi-modal therapy. Polychemotherapy usually provokes a good initial response; however, minimal residual disease with the dissemination of a few resistant tumor cells frequently causes relapse. The number of long-term survivors of high-risk disease has remained unsatisfactorily poor with survival rates as low as 50% after first-line therapy and below 20% in the relapse situation. Applying extensive state-of-the-art methods and workflows for metabolomics and proteomics, this study characterized the modes of action of the metabolic inhibitor L-glyceraldehyde in a panel of neuroblastoma cell lines as well as fibroblasts used as a control. Our analyses revealed that L-glyceraldehyde arrests proliferation and induces neuroblastoma cell death by a multi-modal mechanism that involves oxidative stress and the inhibition of nucleotide biosynthesis. Our data provide the molecular basis for the rationale design of multi-modal therapies involving metabolic targets. 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. [ABSTRACT FROM AUTHOR]