C/EBPβ-LIP mediated activation of the malate-aspartate shuttle sensitizes cells to glycolysis inhibition

Cancer cells use a high glycolytic flux for the generation of metabolic intermediates and ATP needed for cell growth and proliferation. During glycolysis NAD⁺ is reduced to NADH and therefore the NADH/NAD+ ratio in cancer cells is usually high. To sustain a high glycolytic flux NAD⁺ must be regenerated. The mitochondria are major sites of NAD⁺-regeneration where NADH-derived electrons contribute to oxidative respiration and ATP production. Since NAD⁺ and NADH cannot pass the mitochondrial membranes, cells use cytoplasmic-mitochondrial substrate cycles such as the malate-aspartate shuttle (MAS). We show that the glycolysis and the MAS are stimulated by the transcription factor C/EBPβ-LIP, creating dependence on glycolysis for NADH/NAD⁺ homeostasis and cell viability. Inhibition of glycolysis in cells with C/EBPβ-LIP expression results in depletion of NADH and low NADH/NAD⁺ ratios as the MAS continues to oxidize cytosolic NADH into NAD⁺. This condition is associated with cancer cell death. Our data indicate that metabolic reprogramming by C/EBPβ-LIP makes cancer cells vulnerable to glycolytic inhibitors, with possible therapeutic implications.

Tobias Ackermann, Hidde R. Zuidhof, Christine Müller, Gertrud Kortman, Martijn G. S. Rutten, Mathilde Broekhuis, Mohamad Amr Zaini, Götz Hartleben and Cornelis F. Calkhoven.

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C/EBPβ-LIP mediated activation of the malate-aspartate shuttle sensitizes cells to glycolysis inhibition – ClinicalKey