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.

Ursolic acid-mediated changes in glycolytic pathway promote cytotoxic autophagy and apoptosis in phenotypically different breast cancer cells

“…UA-mediated ATP depletion induces energy stress that resulted in AMP-activated protein kinase (AMPK) activation in breast cancer cells that in turn promoted cytotoxic autophagy and apoptosis (this study). UA-induced AMPK activation also contributed to growth inhibition and apoptosis in T24 bladder cancer cells [50] and hepatoma HepG2 cells [51, 52], and autophagy in U87MG glioma cells [37]. More recently, AMPK was found to be a negative regulator of aerobic glycolysis and a suppressor of tumor growth in vivo [53].…”

Suppression of oxidative stress and improvement of liver functions in mice by ursolic acid via LKB1‐AMP‐activated protein kinase signaling

“…It is interesting that UA activates the AMPK pathways in both primary and cancer cells but exerts apoptosis in cancer cells and protects cell death in primary cells . Likewise, UA also induces apoptosis in stellate cells .…”

Anti-hepatocellular carcinoma activity and mechanism of chemopreventive compounds: ursolic acid derivatives

“…Ramos et al (2008) found that UA prevented DNA damage via increase of DNA repair and anti-proliferative properties in HepG2 cells. Lin et al (2011) found that UA reversed the invasion and migration of Hep3B and Huh7 cell lines at 4 lmol/ L. Son et al (2013) reported that UA blocked HepG2 cellular metabolism via AMPK activation and GSK3b phosphorylation, and thus induced apoptosis of HepG2 cells. On the suppression of carcinogenic side, UA could prevent HCC from nonalcoholic fatty liver disease (NAFLD), insulin resistance, inflammation and oxidation stress.…”