The role of ERK 1/2 and p38 MAP-kinase pathways in Taxol-induced apoptosis in human ovarian carcinoma cells
The role of ERK 1/2 and p38 MAP-kinase pathways in Taxol-induced apoptosis in human ovarian carcinoma cells
复制标题
DOI：
10.1006/excr.2001.5262
复制
发表时间：
2001-08-01
影响因子：
3.7
通讯作者：
Wolfson, M
中科院分区：
文献类型：
--
作者：
Seidman, R;Gitelman, I;Wolfson, M
紫杉醇是一种天然来源的抗癌剂，对包括卵巢癌和乳腺癌在内的许多人类癌症具有显著的活性。其细胞毒活性归因于其稳定微管和促进微管组装的能力。最近，人们越来越清楚，紫杉醇有额外的活动，包括在细胞信号传导和基因表达的影响。我们以前已经证明，泰素激活ERK 1/2 MAP激酶，并导致在鼠巨噬细胞样RAW 267.4细胞中形成GRB 2/SHC复合物。在这里，我们证明，紫杉醇激活ERK 1/2和p38 MAP激酶在人卵巢癌细胞具有不同的动力学。在低浓度的紫杉醇（1-100 nM）下，在0.5-6小时内观察到ERK 1/2的活化，而更长时间（24小时）暴露于纳摩尔浓度的紫杉醇导致ERK 1/2磷酸化/活化的消除。高浓度（1-10 μ g/ml）对ERK 1/2活性有明显抑制作用。p38激酶在2小时内被高浓度（1-10 μ M）的Taxol激活，并保持活性超过24小时。动力学研究表明，紫杉醇的这些作用与增殖抑制和凋亡的发生相一致。DA-PI染色可见染色质碎片的出现，琼脂糖凝胶上可见DNA片段，与ERK 1/2活化的减少和活性p38 MAPK水平的伴随增加相一致。抑制剂PD 98059消除了ERK 1/2的激活并增强了紫杉醇的细胞毒性作用。p38激酶的抑制剂SB 203580保护细胞部分免受紫杉醇的侵害，并且出乎意料地激活了ERK 1/2激酶。我们的结论是，ERK 1/2和p38 MAP激酶途径的交替使用可能是必要的过渡，从增殖状态的泰素诱导的人卵巢癌细胞凋亡。(C)北京：科学出版社.
Taxol is an anticancer agent of natural origin with significant activity against a number of human cancers including ovarian and breast carcinomas. Its cytotoxic activity has been attributed to its ability to stabilize microtubules and to promote microtubule assembly. Recently it has become clearer that Taxol has additional activities including effects in cell signaling and gene expression. We have shown previously that Taxol activates ERK 1/2 MAP-kinases and results in the formation of GRB2/SHC complexes in murine macrophage-like RAW 267.4 cells. Here we demonstrate that Taxol activates ERK 1/2 and p38 MAP-kinases in human ovarian carcinoma cells with distinct kinetics. Activation of ERK1/2 has been observed at low concentrations of Taxol (1-100 nM) within 0.5-6 h, whereas longer exposure (24 h) to nanomolar concentrations of Taxol resulted in an abrogation of the ERK1/2 phosphorylation/activation. Higher concentrations (1-10 tcm) resulted in a sharp inhibition of ERK1/2 activity. p38 kinase was activated by high concentrations (1-10 muM) of Taxol within 2 h and remained active for more than 24 h. The kinetic studies showed that these effects of Taxol coincided with an inhibition of proliferation, and the onset of apoptosis. The appearance of the fragmented chromatin visualized by DA-PI staining, and DNA fragments seen on an agarose gel, coincided with the decrease in ERK1/2 activation and concomitant increase of the level of active p38 MAPK. The inhibitor PD98059 abrogated ERK 1/2 activation and increased the cytotoxic effect of Taxol. An inhibitor of p38 kinase, SB203580, protected the cells partially from Taxol and, unexpectedly, activated ERK 1/2 kinases. We conclude that the alternative use of ERK1/2 and p38 MAP-kinase pathways may be necessary for the transition from proliferation state to Taxol-induced apoptosis in human ovarian carcinoma cells. (C) 2001 Academic Press.