Deguelin Suppresses Nalm6 Leukemia Cell Proliferation through Lactate Accumulation and ATP Depletion

Acute lymphoblastic leukemia (ALL) is characterized by metabolic reprogramming, including elevated glycolysis and lactate production, with monocarboxylate transporter 1 (MCT1/SLC16A1) overexpression sustaining glycolytic flux to promote proliferation. Deguelin is a flavonoid compound that has been reported to inhibit several types of cancer. Previous studies indicated that high concentrations of Deguelin suppress cell proliferation by inducing necroptosis, increasing ROS levels, and promoting the phosphorylation of NF-κB and p70S6K. In this study, we found that low concentration of Deguelin inhibit cell proliferation through a different mechanism. Low concentration of Deguelin significantly blocks the cell cycle at the G2/M phase, reduces ROS levels and mitochondrial membrane potential, while not affecting the phosphorylation of NF-κB and p70S6K. Instead, it increases the phosphorylation of GSK-3β and AKT, activating the GSK-3β/AKT signaling pathway to inhibit the proliferation of Nalm6 cells. Additionally, Deguelin reduces the expression of LDHA, resulting in decreased intracellular lactate synthesis, which causes ATP depletion within the cells. Furthermore, Deguelin downregulate the expression of the SLC16A1 gene and the MCT1 protein, reducing lactate influx into the cells, leading to extracellular lactate accumulation and ATP depletion, ultimately leading to impaired cell proliferation.