J Korean Neurosurg Soc.  2009 Oct;46(4):389-396. 10.3340/jkns.2009.46.4.389.

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

Affiliations
  • 1Department of Neurosurgery, Wonkwang University School of Medicine, Iksan, Korea.
  • 2Department of Anesthesiology and Pain Medicine, Wonkwang University School of Medicine, Iksan, Korea.
  • 3Department of Cardiovascular Medicine, Wonkwang University Hospital, Iksan, Korea.
  • 4Department of Biological Science, University of Ulsan College of Medicine, Ulsan, Korea.
  • 5Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, Korea. hopae@wku.ac.kr

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.

Keyword

Triptolide; HT22 hippocampal cell; Mitogen-activated protein kinase phosphatase-1; Extracellular signal-regulated kinase-1/2; Mitogen-activated protein kinase; Proliferation

MeSH Terms

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
Anthracenes
Butadienes
Diterpenes
Epoxy Compounds
Imidazoles
Nitriles
Phenanthrenes
Protein Kinases
Pyridines
RNA, Small Interfering
Vanadates
p38 Mitogen-Activated Protein Kinases
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