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• W4387345052 abstract "Abstract Cancer cells exhibit a unique metabolic preference for choosing the glycolytic pathway over oxidative phosphorylation for maintaining the tumor microenvironment. Lactate dehydrogenase-A (LDH-A) is a key enzyme that facilitates glycolysis by converting pyruvate to lactate and has been shown to be upregulated in multiple cancers due to the hypoxic tumor microenvironment. Diclofenac (DCF), a non-steroidal anti-inflammatory drug, has been shown to exhibit anti-cancer effects by interfering with the glucose metabolism pathway. However, the specific targets remain unknown. Using in-silico , biochemical, and biophysical studies, we show that DCF binds to LDH-A adjacent to the substrate binding site and dose-dependently inhibits its activity in an allosteric manner in HeLa cells. Thus, DCF inhibits the hypoxic microenvironment and induces apoptosis-mediated cell death. DCF fails to induce cytotoxicity in LDH-A knocked-down HeLa cells, confirming that DCF renders its anti-mitotic effects via LDH-A inhibition. DCF-induced LDH-A inhibition alters pyruvate, lactate, NAD + , and ATP production in cells, and this could be a possible mechanism by which DCF inhibits glucose uptake in cancer cells. DCF-induced ATP deprivation leads to mitochondria-mediated oxidative stress, which results in DNA damage, lipid peroxidation, and apoptosis-mediated cell death. Reduction in intracellular ATP levels additionally activates AMPK, a sensor kinase, which further downregulates p-S6K, leading to apoptosis-mediated cell death. We find that in LDH-A knocked-down cells, intracellular ATP levels were depleted, resulting in the inhibition of p-S6K, implying the involvement of DCF-induced LDH-A inhibition in the activation of the AMPK/S6K signaling pathway." @default.
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• W4387345052 date "2023-10-04" @default.
• W4387345052 modified "2023-10-11" @default.
• W4387345052 title "Inhibition of Lactate Dehydrogenase A (LDH-A) by Diclofenac Sodium Induces Apoptosis in HeLa Cells by Activation of AMPK" @default.
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• W4387345052 doi "https://doi.org/10.1101/2023.10.02.560620" @default.
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