Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: inhibition of extracellular signal-regulated kinase activity increases sensitivity to cisplatin.
Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: inhibition of extracellular signal-regulated kinase activity increases sensitivity to cisplatin.
复制标题
DOI：
--
复制
发表时间：
1999-05
期刊：
影响因子：
--
通讯作者：
D. Persons;E. Yazlovitskaya;Wei Cui;J. Pelling
中科院分区：
文献类型：
--
作者：
D. Persons;E. Yazlovitskaya;Wei Cui;J. Pelling
顺铂治疗激活多种信号转导通路，可导致多种细胞反应，包括细胞周期阻滞、DNA修复、存活或凋亡。我们研究了丝裂原活化蛋白激酶、细胞外信号调节激酶1和2 （ERK1/2）、c- jun - n末端激酶1 （JNK1）和p38对顺铂治疗卵巢癌细胞系SK-OV-3的反应。顺铂以剂量依赖的方式诱导ERK1/2和JNK1活性的延迟和延长。ERK1/2和JNK1活性在顺铂治疗开始后24小时内继续增加。相比之下，顺铂治疗对p38活性没有影响。移植在24 h时未能诱导ERK1/2或JNK1，这表明这些激酶的激活依赖于顺铂特异性DNA损伤。环己亚胺治疗可抑制顺铂诱导的ERK1/2活化，表明顺铂诱导的ERK1/2活性依赖于从头蛋白合成。此外，PD 98059抑制顺铂诱导的ERK1/2活性可增强顺铂的细胞毒性。在卵巢癌细胞系UCI 101中，PD 98059治疗后也观察到类似的顺铂增强的细胞毒性作用。这些观察结果表明，顺铂诱导的ERK1/2活化部分保护细胞免受顺铂的细胞毒性。继续研究ERK通路和其他信号转导通路调节顺铂反应的机制可能有助于开发新的策略来改善铂类药物的治疗应用。
Cisplatin treatment activates multiple signal transduction pathways, which can lead to several cellular responses including cell cycle arrest, DNA repair, survival, or apoptosis. We investigated the response of the mitogen-activated protein kinases, extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun-N-terminal kinase 1 (JNK1), and p38, to cisplatin treatment in the ovarian carcinoma cell line SK-OV-3. Cisplatin caused a late and prolonged induction in a dose-dependent manner of both ERK1/2 and JNK1 activity. ERK1/2 and JNK1 activities continued to increase in magnitude up to 24 h following initiation of cisplatin treatment. In contrast, cisplatin treatment had no effect on p38 activity. Transplatin failed to induce either ERK1/2 or JNK1 at 24 h, which suggests that the activation of these kinases was dependent on cisplatin-specific DNA damage. Treatment with cycloheximide resulted in inhibition of cisplatin-induced ERK1/2 activation, demonstrating that ERK1/2 activity induced by cisplatin was dependent on de novo protein synthesis. Furthermore, inhibition of cisplatin-induced ERK1/2 activity by PD 98059 caused enhanced cisplatin cytotoxicity. Similar enhanced cytotoxic effects of cisplatin were also observed following treatment with PD 98059 in the ovarian carcinoma cell line UCI 101. These observations indicate that ERK1/2 activation induced by cisplatin partially protects cells from cisplatin cytotoxicity. Continued investigation into the mechanism by which the ERK pathway and other signal transduction pathways modulate the response to cisplatin may be helpful in the development of new strategies for improving the therapeutic use of platinum drugs.