title: 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: College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Korea.
authors: Hyun-Soo
authors: HS
authors: Son
authors: Hee Young
authors: HY
authors: Kwon
authors: Eun Jung
authors: EJ
authors: Sohn
authors: Jang-Hoon
authors: JH
authors: Lee
authors: Hong-Jung
authors: HJ
authors: Woo
authors: Miyong
authors: M
authors: Yun
authors: Sung-Hoon
authors: SH
authors: Kim
authors: Young-Chul
authors: YC
authors: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008113:Liver Neoplasms / Q000473:pathology; D008301:Maleimides / Q000494:pharmacology; D008565:Membrane Proteins; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D054875:Ubiquitination; D000097245:Ursolic Acid
chemical_list: D055372:AMP-Activated Protein Kinases; D053148:Caspase 3; D015815:Cell Adhesion Molecules; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles; D007976:Leupeptins; D008301:Maleimides; D008565:Membrane Proteins; D011065:Poly(ADP-ribose) Polymerases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016601:RNA-Binding Proteins; D058570:TOR Serine-Threonine Kinases; D014315:Triterpenes; D000097245:Ursolic Acid; C483039:MTDH protein, human; C417521:SB 216763; C546842:MTOR protein, human; C000605506:GSK3B protein, human; C505407:CASP3 protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: AMPK; GSK3β; HepG2 cells; apoptosis; ursolic acid