Inhibitory effect of oleanolic acid on hepatocellular carcinoma via ERK-p53-mediated cell cycle arrest and mitochondrial-dependent apoptosis
Menée in vitro et sur un modèle murin de carcinome hépatocellulaire, cette étude montre que l'acide oléanolique peut inhiber le développement de la tumeur en induisant l'arrêt du cycle cellulaire, impliquant la protéine kinase ERK et le facteur de transcription p53, et l'apoptose dépendante de la voie mitochondriale
Incidence of hepatocellular carcinoma (HCC) is dramatically increasing and is the third cause of cancer death worldwide. One key approach to control HCC is chemoprevention by naturally occurring agents. This study aims at investigating the antitumor effect of oleanolic acid (OA) and the molecular mechanisms. BALB/c mice were injected subcutaneously with HepG2 cells to establish transplanted tumors. Apoptosis and cell cycle arrest-related makers and signaling cascades were determined by western blot, immunofluorescence, RT-PCR and flow cytometric analysis. OA exhibited inhibitory effect on HCC through induction of apoptosis and cell cycle arrest both in transplanted tumors and in HepG2 cells. OA induced apoptosis through mitochondrial pathway, evidenced by inhibition of Akt/mammalian target of rapamycin pathway, mitochondrial dysfunction, transient increase of ATP, increase of Bax/Bcl-2 ratio, increased release of cytochrome c, and activation of caspase/PARP. Activation of mitochondrial apoptotic pathway may be due to ROS generated by mitochondrial fatty acid oxidation, resulted from enhancement of lypolysis regulated by cAMP response element binding protein-hormone-sensitive lipase/PPARγ signaling. OA induced G2/M cell cycle arrest through p21-mediated down-regulation of cyclin B1/cdc2. COX-2 and p53 were involved in OA-exerted effect, and extracellular signal–regulated kinase-p53 signaling played a central role in OA-activated cascades responsible for apoptosis and cell cycle arrest. OA demonstrated significant antitumor activities in HCC in vivo and in vitro models. These data provide new insight into the mechanisms underlying the antitumor effect of OA.
http://carcin.oxfordjournals.org/content/early/2013/02/08/carcin.bgt058.abstract