MAPK signaling pathways regulate mitochondrial-mediated apoptosis induced by isoorientin in human hepatoblastoma cancer cells.

Abstract

Isoorientin (ISO) (CAS RN: 4261-42-1) is a flavonoid compound that can be extracted from several plant species, such as Phyllostachys pubescens, Patrinia, and Drosophyllum lusitanicum. ISO is able to induce apoptosis through mitochondrial dysfunction and inhibition of PI3K/Akt signaling pathway in HepG2 cells, however, the effects of ISO on MAPK signaling pathways remain unknown. The present study investigated the effects of ISO on this pathway, and the roles of MAPK kinases on mitochondrial-mediated apoptosis in HepG2 cells. The results showed that ISO induced cell death in a dose- and time-dependent manner, and induction apoptosis is main cause for ISO-induced cytotoxicity in HepG2 cells. ISO significantly inhibited the levels of ERK1/2 kinase and increased the expression of JNK and p38 kinases. Furthermore, U0126 (an ERK1/2 inhibitor) significantly enhanced the ISO-induced the Bax/Bcl-2 ratio, the release of cytochrome c to the cytosol fraction, and the levels of cleaved caspase-3. While SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor) markedly prevented the expression of these proteins induced by ISO. Furthermore, the ROS inhibitor (NAC) notably promoted the inhibited effect of ISO on the ERK1/2 kinase. NAC also suppressed the p-JNK and p-p38, but failed to reverse the effects of ISO. These results demonstrated for the first time that ISO induces apoptosis in HepG2 cells through inactivating ERK1/2 kinase and activating JNK and p38 kinases, and ROS stimulated by ISO is able to activate the MAPK singaling pathway as the upstream signaling molecules. Initiating event of the mitochondrial-mediated apoptosis induced by ISO is MAPK signals.

• Authors: Li Yuan, Jing Wang, Haifang Xiao, Wanqiang Wu, Yutang Wang, Xuebo Liu
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 53 Pg. 62-8 (Mar 2013) ISSN: 1873-6351 [Electronic] England
• PMID: 23220614 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Anthracenes
• Plant Extracts
• Reactive Oxygen Species
• bcl-2-Associated X Protein
• pyrazolanthrone
• Cytochromes c
• homoorientin
• Phosphatidylinositol 3-Kinases
• p38 Mitogen-Activated Protein Kinases
• CASP3 protein, human
• Caspase 3
• Luteolin

Topics

• Anthracenes (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Caspase 3 (genetics, metabolism)
• Cell Survival (drug effects)
• Cytochromes c (genetics, metabolism)
• Electrophoresis, Polyacrylamide Gel
• Hep G2 Cells
• Hepatoblastoma (drug therapy, pathology)
• Humans
• Luteolin (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Mitochondria (drug effects, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphorylation
• Plant Extracts (pharmacology)
• Reactive Oxygen Species (metabolism)
• bcl-2-Associated X Protein (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (genetics, metabolism)