Activation of reactive oxygen species-mediated mitogen-activated protein kinases pathway regulates both extrinsic and intrinsic apoptosis induced by arctigenin in Hep G2.
OBJECTIVES
Arctigenin (ARG) has been proved to inhibit the viability of hepatocellular carcinoma (HCC) via inducing apoptosis. However, the precise mechanism remains unknown. The present study was aimed to further investigate the mechanism of ARG against HCC in vitro and in vivo.


METHODS
Arctigenin was applied in vitro and in vivo. Western blotting, immunohistochemistry, etc., were used to investigate the mechanisms.


KEY FINDINGS
The time-dependent enhancement of Bax/Bcl-2 ratio, cytochrome c release, Fas and FasL levels, caspase cascade activation and the loss in the mitochondrial out membrane potential indicated that both intrinsic and extrinsic apoptotic pathways were triggered by ARG. Moreover, Jun NH2-terminal kinase (JNK) and p38 phosphorylated time-dependently. And inhibition of the phosphorylation of either p38 or JNK led to a significant reduction in HepG2 apoptosis, owing to the crucial roles of p38 and JNK played in regulating the apoptosis pathways. In addition, ARG increased the generation of reactive oxygen species (ROS) in HepG2 cells, while the antioxidant N-acetyl cysteine almost reversed ARG-induced JNK and p38 activation, and dramatically decreased cell apoptosis. In vivo, ARG increased the cell apoptosis in tumour tissues, and p-p38, p-JNK and Bax were significantly upregulated.


CONCLUSIONS
Our findings demonstrated that ARG induced apoptosis in HCC via ROS-mediated mitogen-activated protein kinases apoptosis pathway.
['Lu|Zheng|Z|https://orcid.org/0000-0003-3277-250X', 'Zhou|Hongbo|H|', 'Zhang|Shishuo|S|', 'Dai|Wei|W|', 'Zhang|Yan|Y|', 'Hong|Liping|L|', 'Chen|Fanjie|F|', 'Cao|Jiyue|J|']
D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D051017:Apoptosis Regulatory Proteins D006528:Carcinoma, Hepatocellular D004789:Enzyme Activation D005663:Furans D056945:Hep G2 Cells D006801:Humans D017705:Lignans D008113:Liver Neoplasms D008807:Mice, Inbred BALB C D008819:Mice, Nude D020928:Mitogen-Activated Protein Kinases D017382:Reactive Oxygen Species D015398:Signal Transduction D047368:Tumor Burden D023041:Xenograft Model Antitumor Assays
mitogen-activated protein kinases apoptosis arctigenin HepG2 reactive oxygen species