Abstract
Aerobic glycolysis is one of the important metabolic characteristics of many malignant tumors. Pyruvate dehydrogenase kinase (PDHK) plays a key role in aerobic glycolysis by phosphorylating the E1α subunit of pyruvate dehydrogenase (PDH). Hence, PDHK has been recognized as a molecular target for cancer treatment. Here, we report that huzhangoside A (Hu.A), a triterpenoid glycoside compound isolated from several plants of the Anemone genus, acts as a novel PDHK inhibitor. Hu.A was found to decrease the cell viability of human breast cancer MDA-MB-231, hepatocellular carcinoma Hep3B, colon cancer HT-29, DLD-1, and murine lewis lung carcinoma LLC cell lines. The activity of PDHK1 was decreased by Hu.A in both in vitro assays and in vivo assays in DLD-1 cells. Hu.A significantly increased the oxygen consumption and decreased the secretory lactate levels in DLD-1 cells. In addition, Hu.A interacted with the ATP-binding pocket of PDHK1 without affecting the interaction of PDHK1 and pyruvate dehydrogenase complex (PDC) subunits. Furthermore, Hu.A significantly induced mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in DLD-1 cells. Consistently, when Hu.A was intraperitoneally injected into LLC allograft mice, the tumor growth was significantly decreased. In conclusion, Hu.A suppressed the growth of tumors in both in vitro and in vivo models via inhibition of PDHK activity.
Highlights
Pyruvate dehydrogenase kinase (PDHK) is a mitochondrial enzyme that suppresses the activity of pyruvate dehydrogenase complex (PDC) by phosphorylating pyruvate dehydrogenase E1α subunit
To investigate whether Hu.A has an inhibitory effect on the kinase activity of PDHK1, we performed an in vitro kinase assay using glutathione S-transferase (GST)-conjugated-PDHK1 and recombinant PDHA protein
We found that Hu.A treatment inhibited the PDHK1 activity in DLD-1 and LLC cells (Figure 2B, and Supplementary Figure S1B)
Summary
Pyruvate dehydrogenase kinase (PDHK) is a mitochondrial enzyme that suppresses the activity of pyruvate dehydrogenase complex (PDC) by phosphorylating pyruvate dehydrogenase E1α subunit. Cancers 2019, 11, 712; doi:10.3390/cancers11050712 www.mdpi.com/journal/cancers (PDHA) [1]. There are four isoforms of PDHK (PHDK1-4) in human and PDC consists of three enzymes including PDHA, dihydrolipoamide acetyltransferase (E2 subunit), and lipoamide dehydrogenase (E3 subunit) [2,3]. PDC activity is crucial for maintaining oxidative phosphorylation (OXPHOS) by converting pyruvate to acetyl-CoA, the first step of the tricarboxylic acid (TCA) cycle [5]. Inhibition of PDC activity is associated with many diseases, including lactic acidosis, diabetes, cerebrovascular and cardiovascular diseases, and cancer [4]. Cancer cells generally prefer glycolysis for producing energy rather than
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