L-Glyceraldehyde inhibits neuroblastoma cell growth via a multi-modal mechanism on metabolism and signaling

ABSTRACT Glyceraldehyde (GA) is a 3-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. This phenomenon was extensively studied up until the 1970’s. 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 cancer cell growth. L-GA induces significant changes in the metabolic profile, promotes oxidative stress and hinders nucleotide biosynthesis. GC-MS and 13 C-labelling 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 the cancer cell. It was confirmed that the redox mechanisms were modulated via L-GA by proteomic analysis. This elucidated a specific subset of proteins harbouring oxidoreductase and antioxidant activity. Analysis of nucleotide pools in L-GA treated cells depicted a remarkable and previously unreported phenotype. Nucleotide biosynthesis in neuroblastoma cells is significantly inhibited upon L-GA treatment. Through the application of the antioxidant N-acetyl-cysteine in conjunction with L-GA, metabolic inhibition was partially relieved. We present novel evidence for the multi-modal mechanism of L-GA action in neuroblastoma cells. Specifically, a simple sugar that inhibits the growth of cancer via dysregulating the fragile homeostatic environment inherent to the cancerous cell.