Modulation of phorbol ester-induced regulation of matrix metalloproteinases and tissue inhibitors of metalloproteinases by SB203580, a specific inhibitor of p38 mitogen-activated protein kinase
Modulation of phorbol ester-induced regulation of matrix metalloproteinases and tissue inhibitors of metalloproteinases by SB203580, a specific inhibitor of p38 mitogen-activated protein kinase
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DOI：
10.3171/jns.2002.97.1.0112
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发表时间：
2002-07-01
影响因子：
4.1
通讯作者：
Lee, SH
中科院分区：
文献类型：
--
作者：
Park, MJ;Park, IC;Lee, SH
Object.基质金属蛋白酶（MMPs）的表达被认为在脑肿瘤侵袭中起核心作用，然而，其潜在机制尚未完全了解。在本研究中，通过评估特异性p38丝裂原活化蛋白激酶（MAPK）抑制剂SB 203580对各种胶质瘤细胞的MMPs分泌和体外侵袭的影响，作者试图确定p38 MAPK通路在调节佛波酯激活的MMPs和金属蛋白酶组织抑制剂（TIMPs）中的作用，（佛波醇-12-肉豆蔻酸酯-13-乙酸酯[PMA]）在D54人胶质母细胞瘤细胞系中的作用。方法。在加入针对这些激酶的磷酸化特异性抗体后，使用Western Not分析确定MAPK的活化。采用明胶酶谱法和Western blot分析MMPs和TIMPs的状态，采用改良的Boyden小室法分析D54细胞和其他胶质瘤细胞的侵袭率。用PMA处理D54细胞激活两种不同的MAPK，细胞外信号调节激酶（ERK）1/2和p38 MAPK。而不是c-Jun N-末端激酶/应激活化蛋白激酶。PMA诱导MMP-9的产生和MMP-2的活化可被p38 MAPK的特异性抑制剂SB 203580阻断，但不能被ERK 1/2的特异性抑制剂PD 98059阻断。此外，PMA诱导的TIMP-1和TIMP-2分泌的下调和MMP-2的主要激活剂膜I型NIMP的上调在这些细胞中被SB 203580逆转。抑制剂还可降低多种胶质瘤细胞系的NIMP分泌和PMA诱导的体外侵袭。这些结果表明，PMA激活p38 MAPK在D54细胞中MMPs和TIMPs的调节中起着中心作用。其在肿瘤侵袭和转移中具有重要影响。此外。SB 203580对p38 MAPK的抑制作用阻断了MMP的分泌和各种胶质瘤细胞的体外侵袭，强调了p38 MAPK抑制剂作为恶性胶质瘤的抗侵袭和/或抗转移剂的可能作用。
Object. Expression of matrix metalloprotemases (MMPs) has been postulated to play a central role in brain tumor invasion however, its underlying mechanism is not yet fully understood. In the present study, by assessing the effect of a specific p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, on the secretion of MMPs and in vitro invasion of various glioma cells, the authors attempt to define the role of the p38 MAPK pathway in the regulation of MMPs and tissue inhibitors of metalloproteinases (TIMPs) activated by phorbol ester (phorbol-12-myristate-13-acetate [PMA]) in the D54 human glioblastoma cell line.Methods. The activation of MAPKs was determined using Western Not analysis after addition of phospho-specific antibodies against these kinases. the Status of MMPs and TIMPs was analyzed using gelatin zymography and Western blot analysis, and the invasion rate of D54 cells and other glioma cells was analyzed using a modified Boyden chamber assay. Treatment of D54 cells with PMA activated two distinct MAPKs, extracellular sinal-regulated kinase (ERK) 1/2 and p38 MAPK. but not c-Jun N-terminal kinase/stress-activated protein kinase. Induction of MMP-9 production and MMP-2 activation by PMA were blocked by SB203580, a specific inhibitor of p38 MAPK, but not by PD98059, a specific inhibitor of ERK 1/2. In addition, PMA-induced downregulation of TIMP-1 and TIMP-2 secretion and upregulation of the membrane type I NIMP, a major activator of MMP-2 on the cell Surface, were reversed by SB203580 in these cell the PMA-induced increase of invasion in vitro decreased when SB203580 was added to the top compartment of a modified Boyden chamber; and the inhibitor also reduced the NIMP secretion and PMA-induced in vitro invasion in various glioma cell lines.Conclusions. These results indicate that activation of p38 MAPK by PMA plays a central role in the regulation of MMPs and TIMPs in D54 cells. which has a major influence in tumor invasion and metastasis. Furthermore. inhibition of p38 MAPK by SB203580 blocked the secretion of MMPs and in vitro invasion of various glioma cells, underscoring a possible role of p38 MAPK inhibitors as antiinvasive and/or antimetastatic agents of malignant gliomas.