Browse > Article
http://dx.doi.org/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  

Koo, Hee-Sang (Department of Neurosurgery, Wonkwang University School of Medicine)
Kang, Sung-Don (Department of Neurosurgery, Wonkwang University School of Medicine)
Lee, Ju-Hwan (Department of Anesthesiology and Pain Medicine, Wonkwang University School of Medicine)
Kim, Nam-Ho (Department of Cardiovascular Medicine, Wonkwang University Hospital)
Chung, Hun-Taeg (Department of Biological Science, University of Ulsan College of Medicine)
Pae, Hyun-Ock (Department of Microbiology and Immunology, Wonkwang University School of Medicine)
Publication Information
Journal of Korean Neurosurgical Society / v.46, no.4, 2009 , pp. 389-396 More about this Journal
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.
Keywords
Triptolide; HT22 hippocampal cell; Mitogen-activated protein kinase phosphatase-1; Extracellular signal-regulated kinase-1/2; Mitogen-activated protein kinase; Proliferation;
Citations & Related Records

Times Cited By Web Of Science : 3  (Related Records In Web of Science)
Times Cited By SCOPUS : 2
연도 인용수 순위
1 Burke RE : Inhibition of mitogen-activated protein kinase and stimulation of Akt kinase signaling pathways : two approaches with therapeutic potential in the treatment of neurodegenerative disease. Pharmacol Ther 114 : 261-277, 2007   DOI   ScienceOn
2 Jiao J, Xue B, Zhang L, Gong Y, Li K, Wang H, et al. : Triptolide inhibits amyloid-beta1-42-induced TNF-alpha and IL-1beta production in cultured rat microglia. J Neuroimmunol 205 : 32-36, 2008   DOI   ScienceOn
3 Orton RJ, Sturm OE, Vyshemirsky V, Calder M, Gilbert DR, Kolch W : Computational modeling of the receptor-tyrosine-kinaseactivated MAPK pathway. Biochem J 392 : 249-261, 2005   DOI   ScienceOn
4 Owens DM, Keyse SM : Differential regulation of MAP kinase signaling by dual-specificity protein phosphatases. Oncogene 26 : 3203-3213, 2007   DOI   ScienceOn
5 Shepherd EG, Zhao Q, Welty SE, Hansen TN, Smith CV, Liu Y : The function of mitogen-activated protein kinase phosphatase-1 in peptidoglycan-stimulated macrophages. J Biol Chem 279 : 54023-54031, 2004   DOI   ScienceOn
6 Wu JJ, Bennett AM : Essential role for mitogen-activated protein (MAP) kinase phosphatase-1 in stress-responsive MAP kinase and cell survival signaling. J Biol Chem 280 : 16461-16466, 2005   DOI   ScienceOn
7 Zhao Q, Shepherd EG, Manson ME, Nelin LD, Sorokin A, Liu Y : The role of mitogen-activated protein kinase phosphatase-1 in the response of alveolar macrophages to lipopolysaccharide : attenuation of proinflammatory cytokine biosynthesis via feedback control of p38. J Biol Chem 280 : 8101-8108, 2005   DOI   ScienceOn
8 Miloso M, Scuteri A, Foudah D, Tredici G : MAPKs as mediators of cell fate determination : an approach to neurodegenerative diseases. Curr Med Chem 15 : 538-548, 2008   DOI   ScienceOn
9 Serini S, Trombino S, Oliva F, Piccioni E, Monego G, Resci F, et al. : Docosahexaenoic acid induces apoptosis in lung cancer cells by increasing MKP-1 and down-regulating p-ERK1/2 and p-p38 expression. Apoptosis 13 : 1172-1183, 2008   DOI   ScienceOn
10 Kim DW, Ahan SH, Kim TY : Enhancement of Arsenic Trioxide (As2O3)- Mediated Apoptosis Using Berberine in Human Neuroblastoma SH-SY5Y Cells. J Korean Neurosurg Soc 42 : 392-399, 2007   DOI   ScienceOn
11 Miyata Y, Sato T, Ito A : Triptolide, a diterpenoid triepoxide, induces antitumor proliferation via activation of c-Jun NH2-terminal kinase 1 by decreasing phosphatidylinositol 3-kinase activity in human tumor cells. Biochem Biophys Res Commun 336 : 1081-1086, 2005   DOI   ScienceOn
12 Frederiksen K, Jat JS, Valtz N, Levy D, McKay R : Immortalization of precursor cells from the mammalian CNS. Neuron 1 : 439-448, 1988   DOI   ScienceOn
13 Pan MR, Chang HC, Hung WC : Non-steroidal anti-inflammatory drugs suppress the ERK signaling pathway via block of Ras/c-Raf interaction and activation of MAP kinase phosphatases. Cell Signal 20 : 1134-1141, 2008   DOI   ScienceOn
14 Cerignoli F, Rahmouni S, Ronai Z, Mustelin T : Regulation of MAP kinases by the VHR dual-specific phosphatase : implications for cell growth and differentiation. Cell Cycle 5 : 2210-2215, 2006   DOI
15 Gao JP, Sun S, Li WW, Chen YP, Cai DF : Triptolide protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats : implication for immunosuppressive therapy in Parkinson's disease. Neurosci Bull 24 : 133-142, 2008   DOI   ScienceOn
16 Li B, Yang L, Shen J, Wang C, Jiang Z : The antiproliferative effect of sildenafil on pulmonary artery smooth muscle cells is mediated via upregulation of mitogen-activated protein kinase phosphatase-1 and degradation of extracellular signal-regulated kinase 1/2 phosphorylation. Anesth Analg 105 : 1034-1041, 2007   DOI   ScienceOn
17 Mebratu Y, Tesfaigzi Y : How ERK1/2 activation controls cell proliferation and cell death is subcellular localization the answer? Cell Cycle 8 : 1168-1175, 2009   DOI   ScienceOn
18 Chen P, Li J, Barnes J, Kokkonen GC, Lee JC, Liu Y : Restraint of Proinflammatory cytokine biosynthesis by mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages. J Immunol 169 : 6408-6416, 2002   ScienceOn
19 Nicolini G, Rigolio R, Scuteri A, Miloso M, Saccomanno D, Cavaletti G, et al. : Effect of trans-resveratrol on signal transduction pathways involved in paclitaxel-induced apoptosis in human neuroblastoma SH-SY5Y cells. Neurochem Int 42 : 419-429, 2003   DOI   ScienceOn
20 Zhao G, Vaszar LT, Qiu D, Shi L, Kao PN : Anti-inflammatory effects of triptolide in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 279 : L958-L966, 2000
21 Kiviharju TM, Lecane PS, Sellers RG, Peehl DM : Antiproliferative and proapoptotic activities of triptolide (PG490), a natural product entering clinical trials, on primary cultures of human prostatic epithelial cells. Clin Cancer Res 8 : 2666-2674, 2002   ScienceOn
22 Palm-Leis A, Singh US, Herbelin BS, Olsovsky GD, Baker KM, Pan J : Mitogen-activated protein kinases and mitogen-activated protein kinase phosphatases mediate the inhibitory effects of all-trans retinoic acid on the hypertrophic growth of cardiomyocytes. J Biol Chem 279 : 54905-54917, 2004   DOI   ScienceOn
23 Keyse SM : Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev 27 : 253-261, 2008   DOI   ScienceOn
24 Chen LW, Wang YQ, Wei LC, Shi M, Chan YS : Chinese herbs and herbal extracts for neuroprotection of dopaminergic neurons and potential therapeutic treatment of Parkinson's disease. CNS Neurol Disord Drug Targets 6 : 273-281, 2007   DOI   ScienceOn
25 Valledor AF, Arpa L, Sánchez-Tilló E, Comalada M, Casals C, Xaus J, et al. : IFN-$\gamma$-mediated inhibition of MAPK phosphatase expression results in prolonged MAPK activity in response to M-CSF and inhibition of proliferation. Blood 112 : 3274-3282, 2008   DOI   ScienceOn
26 Boutros T, Chevet E, Metrakos P : Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation : roles in cell growth, death, and cancer. Pharmacol Rev 60 : 261-310, 2008   DOI   ScienceOn
27 Pae HO, Jeong SO, Zheng M, Ha HY, Lee KM, Kim EC, et al. : Curcumin attenuates ethanol-induced toxicity in HT22 hippocampal cells by activating mitogen-activated protein kinase phosphatase-1. Neurosci Lett 453 : 186-189, 2009   DOI   ScienceOn
28 Zhou Y, Ling EA, Dheen ST : Dexamethasone suppresses monocyte chemoattractant protein-1 production via mitogen activated protein kinase phosphatase-1 dependent inhibition of Jun N-terminal kinase and p38 mitogen-activated protein kinase in activated rat microglia. J Neurochem 102 : 667-678, 2007   DOI   ScienceOn
29 Li X, Schwacha MG, Chaudry IH, Choudhry MA : A role of PP1/PP2A in mesenteric lymph node T cell suppression in a two-hit rodent model of alcohol intoxication and injury. J Leukoc Biol 79 : 453-462, 2006   DOI   ScienceOn