Momordin Ic induces HepG2 cell apoptosis through MAPK and PI3K/Akt-mediated mitochondrial pathways.

Abstract

Momordin Ic is a natural triterpenoid saponin enriched in various Chinese and Japanese natural medicines such as the fruit of Kochia scoparia (L.) Schrad. So far, there is little scientific evidence for momordin Ic with regard to the anti-tumor activities. The aim of this work was to elucidate the anti-tumor effect of momordin Ic and the signal transduction pathways involved. We found that momordin Ic induced apoptosis in human hepatocellular carcinoma HepG2 cells, which were supported by DNA fragmentation, caspase-3 activation and PARP cleavage. Meanwhile, momordin Ic triggered reactive oxygen species (ROS) production together with collapse of mitochondrial membrane potential, cytochrome c release, down-regulation of Bcl-2 and up-regulation of Bax expression. The activation of p38 and JNK, inactivation of Erk1/2 and Akt were also demonstrated. Although ROS production rather than NO was stimulated, the expression of iNOS and HO-1 were altered after momordin Ic treatment for 4 h. Furthermore, the cytochrome c release, caspase-3 activation, Bax/Bcl-2 expression and PARP cleavage were promoted with LY294002 and U0126 intervention but were blocked by SB203580, SP600125, PI3K activator, NAC and 1,400 W pretreatment, demonstrating the mitochondrial disruption. Furthermore, momordin Ic combination with NAC influenced MAPK, PI3K/Akt and HO-1, iNOS pathways, MAPK and PI3K/Akt pathways also regulated the expression of HO-1 and iNOS. These results indicated that momordin Ic induced apoptosis through oxidative stress-regulated mitochondrial dysfunction involving the MAPK and PI3K-mediated iNOS and HO-1 pathways. Thus, momordin Ic might represent a potential source of anticancer candidate.

• Authors: Jing Wang, Li Yuan, Haifang Xiao, Chunxia Xiao, Yutang Wang, Xuebo Liu
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 18 Issue 6 Pg. 751-65 (Jun 2013) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 23417763 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• momordin I (Oleanolic Acid)
• Oleanolic Acid
• NOS2 protein, human
• Nitric Oxide Synthase Type II
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Caspase 3

Topics

• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Survival (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Hep G2 Cells
• Humans
• Mitochondria (drug effects, physiology)
• Nitric Oxide Synthase Type II (biosynthesis)
• Oleanolic Acid (analogs & derivatives, pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)