Triptolide Inhibits the Proliferation of Immortalized HT22 Hippocampal Cells Via Persistent Activation of Extracellular Signal-Regulated Kinase-1/2 by Down-Regulating Mitogen-Activated Protein Kinase Phosphatase-1 Expression.
10.3340/jkns.2009.46.4.389
- Author:
Hee Sang KOO
1
;
Sung Don KANG
;
Ju Hwan LEE
;
Nam Ho KIM
;
Hun Taeg CHUNG
;
Hyun Ock PAE
Author Information
1. Department of Neurosurgery, Wonkwang University School of Medicine, Iksan, Korea.
- Publication Type:Original Article
- Keywords:
Triptolide;
HT22 hippocampal cell;
Mitogen-activated protein kinase phosphatase-1;
Extracellular signal-regulated kinase-1/2;
Mitogen-activated protein kinase;
Proliferation
- MeSH:
Anthracenes;
Blotting, Western;
Butadienes;
Cell Proliferation;
Diterpenes;
Down-Regulation;
Epoxy Compounds;
Imidazoles;
Neurons;
Nitriles;
p38 Mitogen-Activated Protein Kinases;
Phenanthrenes;
Phosphorylation;
Protein Kinases;
Pyridines;
RNA, Small Interfering;
Vanadates
- From:Journal of Korean Neurosurgical Society
2009;46(4):389-396
- CountryRepublic of Korea
- Language:English
-
Abstract:
OBJECTIVE: Triptolide (TP) has been reported to suppress the expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), of which main function is to inactivate the extracellular signal-regulated kinase-1/2 (ERK-1/2), the p38 MAPK and the c-Jun N-terminal kinase-1/2 (JNK-1/2), and to exert antiproliferative and pro-apoptotic activities. However, the mechanisms underlying antiproliferative and pro-apoptotic activities of TP are not fully understood. The purpose of this study was to examine whether the down-regulation of MKP-1 expression by TP would account for antiproliferative activity of TP in immortalized HT22 hippocampal cells. METHODS: MKP-1 expression and MAPK phosphorylation were analyzed by Western blot. Cell proliferation was assessed by 3H-thymidine incorporation. Small interfering RNA (siRNA) against MKP-1, vanadate (a phosphatase inhibitor), U0126 (a specific inhibitor for ERK-1/2), SB203580 (a specific inhibitor for p38 MAPK), and SP600125 (a specific inhibitor for JNK-1/2) were employed to evaluate a possible mechanism of antiproliferative action of TP. RESULTS: At its non-cytotoxic dose, TP suppressed MKP-1 expression, reduced cell growth, and induced persistent ERK-1/2 activation. Similar growth inhibition and ERK-1/2 activation were observed when MKP-1 expression was blocked by MKP-1 siRNA and its activity was inhibited by vanadate. The antiproliferative effects of TP, MKP-1 siRNA, and vanadate were significantly abolished by U0126, but not by SB203580 or SP600125. CONCLUSION: Our findings suggest that TP inhibits the growth of immortalized HT22 hippocampal cells via persistent ERK-1/2 activation by suppressing MKP-1 expression. Additionally, this study provides evidence supporting that MKP-1 may play an important role in regulation of neuronal cell growth.
