Antroquinonol displays anticancer potential against human hepatocellular carcinoma cells: A crucial role of AMPK and mTOR pathways
Journal
Biochemical Pharmacology
Journal Volume
79
Journal Issue
2
Pages
162-171
Date Issued
2010
Author(s)
Abstract
5′AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) are two serine/threonine protein kinases responsible for cellular energy homeostasis and translational control, respectively. Evidence suggests that these two kniases are potential targets for cancer chemotherapy against hepatocellular carcinoma (HCC). Antroquinonol that is isolated from Antrodia camphorate, a well-known Traditional Chinese Medicine for treatment of liver diseases, displayed effective anticancer activity against both HBV DNA-positive and -negative HCC cell lines. The rank order of potency against HCCs is HepG2 > HepG2.2.15 > Mahlavu > PLC/PRF/5 > SK-Hep1 > Hep3B. Antroquinonol completely abolished cell-cycle progression released from double-thymidine-block synchronization and caused a subsequent apoptosis. The data were supported by down-regulation and reduced nuclear translocation of G1-regulator proteins, including cyclin D1, cyclin E, Cdk4 and Cdk2. Further analysis showed that the mRNA expressions of the G1-regulator proteins were not modified by antroquinonol, indicating an inhibition of translational but not transcriptional levels. Antroquinonol induced the assembly of tuberous sclerosis complex (TSC)-1/TSC2, leading to the blockade of cellular protein synthesis through inhibition of protein phosphorylation including mTOR (Ser2448), p70S6K (Thr421/Ser424 and Thr389) and 4E-BP1 (Thr37/Thr46 and Thr70). Furthermore, the AMPK activity was elevated by antroquinonol. Compound C, a selective AMPK inhibitor, significantly reversed antroquinonol-mediated effects suggesting the crucial role of AMPK. Besides, the loss of mitochondrial membrane potential and depletion of mitochondrial content indicated the mitochondrial stress caused by antroquinonol. In summary, the data suggest that antroquinonol displays anticancer activity against HCCs through AMPK activation and inhibition of mTOR translational pathway, leading to G1 arrest of the cell-cycle and subsequent cell apoptosis. ? 2009 Elsevier Inc. All rights reserved.
SDGs
Other Subjects
antineoplastic agent; antroquinonol; cyclin D1; cyclin dependent kinase 2; cyclin dependent kinase 4; cyclin E; hydroxymethylglutaryl coenzyme A reductase kinase; initiation factor 4E binding protein 1; mammalian target of rapamycin; messenger RNA; mitochondrial DNA; protein p70; regulator protein; serine; threonine; tuberin; unclassified drug; antineoplastic activity; Antrodia camphorate; apoptosis; article; cancer inhibition; cell cycle arrest; cell cycle G1 phase; cell cycle progression; cell strain HepG2; Chinese herb; Chinese medicine; clinical effectiveness; controlled study; down regulation; drug potency; enzyme activation; enzyme activity; gene expression regulation; human; human cell; liver cell carcinoma; mitochondrial DNA depletion; mitochondrial membrane potential; priority journal; protein assembly; protein induction; protein phosphorylation; protein synthesis inhibition; translation regulation; Adenylate Kinase; Base Sequence; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; DNA Primers; Flow Cytometry; Humans; Liver Neoplasms; Phosphorylation; Protein Kinases; Reverse Transcriptase Polymerase Chain Reaction; TOR Serine-Threonine Kinases; Ubiquinone
Type
journal article