Abstract
Malic enzyme 1 (ME1) regulates one of the main pathways that provide nicotinamide adenine dinucleotide phosphate (NADPH), which is essential for cancer cell growth through maintenance of redox balance and biosynthesis processes in the cytoplasm. In this study, we found that ME1 inhibition disrupted metabolism in cancer cells and inhibited cancer cell growth by inducing senescence or apoptosis. In glucose-restricted culture conditions, cancer cells increased ME1 expression, and tracer experiments with labelled glutamine revealed that the flux of ME1-derived pyruvate to citrate was enhanced. In addition, cancer cells showed higher sensitivity to ME1 depletion in glucose-restricted conditions compared to normal culture conditions. These results suggest that in a low-glucose environment, where glycolysis and the pentose phosphate pathway (PPP) is attenuated, cancer cells become dependent on ME1 for the supply of NADPH and pyruvate. Our data demonstrate that ME1 is a promising target for cancer treatment, and a strategy using ME1 inhibitors combined with inhibition of glycolysis, PPP or redox balance regulators may provide an effective therapeutic option.
Highlights
In malignant tumours, oncogenic gene alterations such as point mutations, translocations and gene amplification and deletion are recurrently observed, and the oncogenes and their downstream signals have been targeted for cancer therapy.[1]
nicotinamide adenine dinucleotide phosphate (NADPH) is produced by metabolic enzymes such as glucose-6phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) of the pentose phosphate pathway (PPP), malic enzymes (MEs), isocitrate dehydrogenases (IDHs) and enzymes in one-carbon-tetrahydrofolate oxidation pathways
U2OS cells were transfected with Malic enzyme 1 (ME1), ME 2 (ME2) or ME 3 (ME3) cDNAs and immuno-stained with each antibody; mitochondria were stained with Mito-Tracker
Summary
Oncogenic gene alterations such as point mutations, translocations and gene amplification and deletion are recurrently observed, and the oncogenes and their downstream signals have been targeted for cancer therapy.[1]. Cancer-associated metabolic reprogramming affects gene expression, cellular differentiation and tumour microenvironment, and these characteristics were recently summarised by Pavlova NN et al.[4] as the six hallmarks of cancer metabolism. NADPH is produced by metabolic enzymes such as glucose-6phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) of the pentose phosphate pathway (PPP), malic enzymes (MEs), isocitrate dehydrogenases (IDHs) and enzymes in one-carbon-tetrahydrofolate oxidation pathways. These NADPH-producing enzymes have been evaluated as potential therapeutic targets of cancer.[5,6,7]. We explored the use of ME1 as a target of cancer treatment through testing the vulnerability of cancer cells to ME1 inhibition by analysing the resulting alterations in gene expression and metabolite levels
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