Activation of AMP-activated protein kinase and phosphorylation of glycogen synthase kinase3 β mediate ursolic acid induced apoptosis in HepG2 liver cancer cells.

Abstract	Despite the antitumour effect of ursolic acid observed in several cancers, the underlying mechanism remains unclear. Thus, in the present study, the roles of AMP-activated protein kinase (AMPK) and glycogen synthase kinase 3 beta (GSK3β) were examined in ursolic acid induced apoptosis in HepG2 hepatocellular carcinoma cells. Ursolic acid significantly exerted cytotoxicity, increased the sub-G1 population and the number of ethidium homodimer and terminal deoxynucleotidyl transferase(TdT) mediated dUTP nick end labeling positive cells in HepG2 cells. Also, ursolic acid enhanced the cleavages of poly-ADP-ribose polymerase (PARP) and caspase3, attenuated the expression of astrocyte elevated gene (AEG1) and survivin in HepG2 cells. Interestingly, ursolic acid increased the phosphorylation of AMPK and coenzyme A carboxylase and also enhanced phosphorylation of GSK3β at inactive form serine 9, whereas ursolic acid attenuated the phosphorylation of AKT and mTOR in HepG2 cells. Conversely, AMPK inhibitor compound C or GSK3β inhibitor SB216763 blocked the cleavages of PARP and caspase 3 induced by ursolic acid in HepG2 cells. Furthermore, proteosomal inhibitor MG132 suppressed AMPK activation, GSK3β phosphorylation, cleaved PARP and deceased AEG-1 induced by ursolic acid in HepG2 cells. Overall, our findings suggest that ursolic acid induced apoptosis in HepG2 cells via AMPK activation and GSK3β phosphorylation as a potent chemopreventive agent.
Authors	Hyun-Soo Son, Hee Young Kwon, Eun Jung Sohn, Jang-Hoon Lee, Hong-Jung Woo, Miyong Yun, Sung-Hoon Kim, Young-Chul Kim
Journal	Phytotherapy research : PTR (Phytother Res) Vol. 27 Issue 11 Pg. 1714-22 (Nov 2013) ISSN: 1099-1573 [Electronic] England
PMID	23325562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2013 John Wiley & Sons, Ltd.
Chemical References	Cell Adhesion Molecules Indoles Leupeptins MTDH protein, human Maleimides Membrane Proteins Protein Kinase Inhibitors RNA-Binding Proteins SB 216763 Triterpenes Poly(ADP-ribose) Polymerases MTOR protein, human GSK3B protein, human Glycogen Synthase Kinase 3 beta Proto-Oncogene Proteins c-akt TOR Serine-Threonine Kinases Glycogen Synthase Kinase 3 AMP-Activated Protein Kinases CASP3 protein, human Caspase 3 benzyloxycarbonylleucyl-leucyl-leucine aldehyde
Topics	AMP-Activated Protein Kinases (metabolism) Apoptosis (drug effects) Carcinoma, Hepatocellular (pathology) Caspase 3 (metabolism) Cell Adhesion Molecules (metabolism) Glycogen Synthase Kinase 3 (metabolism) Glycogen Synthase Kinase 3 beta Hep G2 Cells Humans Indoles (pharmacology) Leupeptins (pharmacology) Liver Neoplasms (pathology) Maleimides (pharmacology) Membrane Proteins Phosphorylation Poly(ADP-ribose) Polymerases (metabolism) Protein Kinase Inhibitors (pharmacology) Proto-Oncogene Proteins c-akt (metabolism) RNA-Binding Proteins TOR Serine-Threonine Kinases (metabolism) Triterpenes (pharmacology) Ubiquitination Ursolic Acid

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