Inhibition of malic enzyme 1 disrupts cellular metabolism and leads to vulnerability in cancer cells in glucose-restricted conditions

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.

Inhibition of glycolysis disrupts cellular antioxidant defense and sensitizes HepG2 cells to doxorubicin treatment

“…GLUT1, glucose transporter 1; HK2, hexokinase 2; LDHA, lactate dehydrogenase A; PCK2, phosphoenolpyruvate carboxykinase 2; PDK1, pyruvate dehydrogenase kinase 1; NNT, nicotinamide nucleotide transhydrogenase; SOD2, superoxide dismutase 2; GPX1, glutathione peroxidase 1. glycolysis and glutaminolysis seem to be multifactorial and remain controversial [38]. Our results seem to be in agreement with the study of Murai et al [39] in which the authors stated that cancer cells in glucoserestricted conditions become dependent on glutamine and malic enzyme for the supply of NADPH and pyruvate. In our study, the HepG2 cells had a reduced ability to take up glutamine only when both DOX and a glycolysis inhibitor acted together and, interestingly, regardless of the type of inhibitor and its particular mechanism of action.…”

“…Our results seem to be in agreement with the study of Murai et al . in which the authors stated that cancer cells in glucose‐restricted conditions become dependent on glutamine and malic enzyme for the supply of NADPH and pyruvate. In our study, the HepG2 cells had a reduced ability to take up glutamine only when both DOX and a glycolysis inhibitor acted together and, interestingly, regardless of the type of inhibitor and its particular mechanism of action.…”

Malic enzyme 1 is a potential marker of combined hepatocellular cholangiocarcinoma, subtype with stem‐cell features, intermediate‐cell type

“…revealed that ME1 enhances the pentose phosphate pathway, which is another major route for generating cellular NADPH, through direct binding and activating 6‐phosphogluconate dehydrogenase . Recent studies have revealed that various human cancers, including HCC, express ME1 . Through these metabolic systems, ME1 might contribute to protect cancer cells from reactive oxygen species, which induce cellular damage and could play an important role in the survival of cancer cells and treatment resistance .…”

“…Recent studies have revealed that various human cancers, including HCC, express ME1 . Through these metabolic systems, ME1 might contribute to protect cancer cells from reactive oxygen species, which induce cellular damage and could play an important role in the survival of cancer cells and treatment resistance . Furthermore, it is thought that ME1 participates in the migratory ability of cancer cells by promoting epithelial–mesenchymal transition .…”

“…Recent studies reported that ME1 metabolism is regulated by a mutation of major oncogenes or antioncogenes, such as KRAS , myc , or TP53 . Liu et al .…”