Inhibition of extracellular signal-regulated protein kinase or c-Jun N-terminal protein kinase cascade, differentially activated by cisplatin, sensitizes human ovarian cancer cell line
Inhibition of extracellular signal-regulated protein kinase or c-Jun N-terminal protein kinase cascade, differentially activated by cisplatin, sensitizes human ovarian cancer cell line
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DOI：
10.1074/jbc.274.44.31648
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发表时间：
1999-10-29
影响因子：
4.8
通讯作者：
Murata, Y
中科院分区：
文献类型：
--
作者：
Hayakawa, J;Ohmichi, M;Murata, Y
我们研究了c-Jun N-末端蛋白激酶（JNK）和细胞外信号调节蛋白激酶（ERK）级联在人卵巢癌顺铂耐药细胞Caov-5和顺铂敏感细胞A2780中的作用。用顺铂而不是反铂异构体处理两种细胞激活JNK和ERK。顺铂激活JNK发生在30 min，在3 h达到平台，此后下降，而顺铂激活ERK显示出双相模式，表明不同的时间范围。顺铂对JNK的激活在1000 μ M时最大，而ERR的激活在100 μ M时最大，在较高浓度时较小，表明不同的剂量依赖性。顺铂诱导的JNK激活既不是细胞外的，也不是细胞内的Ca 2+。也不依赖于蛋白激酶C，而顺铂诱导的ERK激活是细胞外和细胞内Ca 2+依赖性和蛋白激酶C依赖性的。丝裂原活化蛋白激酶/细胞外信号调节激酶激酶抑制剂PD 98059对顺铂诱导的JNK活性没有影响，表明ERR和JNK级联之间没有串扰。我们进一步检查了顺铂治疗后每个级联对生存力的影响。无论是显性阴性c-Jun的外源性表达还是PD 98059的处理都诱导了两种细胞对顺铂的敏感性。我们的研究结果表明，顺铂诱导的DNA损伤差异激活JNK和ERK级联，抑制这些级联敏感卵巢癌细胞顺铂。
We have studied the roles of c-Jun N-terminal protein kinase (JNK) and extracellular signal-regulated protein kinase (ERK) cascade in both the cisplatin-resistant Caov-5 and the cisplatin-sensitive A2780 human ovarian cancer cell Lines. Treatment of both cells with cisplatin but not transplatin isomer activates JNK and ERK, Activation of JNK by cisplatin occurred at 30 min, reached a plateau at 3 h, and declined thereafter, whereas activation of ERK by cisplatin showed a biphasic pattern, indicating the different time frame. Activation of JNK by cisplatin was maximal at 1000 mu M,whereas activation of ERR was maximal at 100 mu M and was less at higher concentrations, indicating the different dose dependence. Cisplatin-induced JNK activation was neither extracellular and intracellular Ca2+. nor protein kinase C-dependent, whereas cisplatin-induced ERK activation was extracellular and intracellular Ca2+- dependent and protein kinase C-dependent. A mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor, PD98059, had no effect on the cisplatin-induced JNK activity, suggesting an absence of cross-talk between the ERR and JNK cascades. We further examined the effect of each cascade on the viability following cisplatin treatment. Either exogenous expression of dominant negative c-Jun or the treatment by PD98059 induced sensitivity to cisplatin in both cells. Our findings suggest that cisplatin-induced DNA damage differentially activates JNK and ERK cascades and that inhibition of either of these cascades sensitizes ovarian cancer cells to cisplatin.