Abstract
Pyruvate dehydrogenase kinase PDK1 is a metabolic enzyme responsible for switching glucose metabolism from mitochondrial oxidation to aerobic glycolysis in cancer cells, a general hallmark of malignancy termed the Warburg effect. Herein we report the identification of JX06 as a selective covalent inhibitor of PDK1 in cells. JX06 forms a disulfide bond with the thiol group of a conserved cysteine residue (C240) based on recognition of a hydrophobic pocket adjacent to the ATP pocket of the PDK1 enzyme. Our investigations of JX06 mechanism suggested that covalent modification at C240 induced conformational changes at Arginine 286 through Van der Waals forces, thereby hindering access of ATP to its binding pocket and in turn impairing PDK1 enzymatic activity. Notably, cells with a higher dependency on glycolysis were more sensitive to PDK1 inhibition, reflecting a metabolic shift that promoted cellular oxidative stress and apoptosis. Our findings offer new mechanistic insights including how to therapeutically target PDK1 by covalently modifying the C240 residue.
Highlights
Cancer cells feature a unique metabolic profile of high aerobic glycolysis, known as "Warburg effect," which describes the phenomenon of the enhanced conversion of glucose into lactate even in the presence of oxygen [1]
To examine whether JX06 targeted pyruvate dehydrogenase kinase (PDK), JX06 activity was profiled in a board panel of 323 kinases, which covered most known kinases implicated in cancer malignancy (Supplementary Table S3)
In an effort to examine the cellular impacts of JX06 in human cancer cells, we unexpectedly discovered that cancer cell lines exhibited distinct outcomes in reactive oxygen species (ROS) generation caused by JX06, despite inhibited PDK1 signaling (Fig. 2A and Supplementary Fig. S3)
Summary
Cancer cells feature a unique metabolic profile of high aerobic glycolysis, known as "Warburg effect," which describes the phenomenon of the enhanced conversion of glucose into lactate even in the presence of oxygen [1]. Aerobic glycolysis confers a significant growth advantage of cancer cells by supplying essential ATP production, generating precursors for biosynthesis, and providing reducing equivalents for antioxidant defense [2, 3]. Warburg effect has been observed for decades, how cancer cells gain this unique metabolic profile remains unclear [4, 5]. Mitochondrial pyruvate dehydrogenase kinase (PDK) functions as a molecular switch that diminishes mitochondrial res-. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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