Hayakawa J, Ohmichi M, Kurachi H, Ikegami H, Kimura A, Matsuoka T, Jikihara H, Mercola D, Murata Y
Department of Obstetrics, Osaka University Medical School, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
J Biol Chem. 1999 Oct 29;274(44):31648-54. doi: 10.1074/jbc.274.44.31648.
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-3 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 microM, whereas activation of ERK was maximal at 100 microM and was less at higher concentrations, indicating the different dose dependence. Cisplatin-induced JNK activation was neither extracellular and intracellular Ca(2+)- nor protein kinase C-dependent, whereas cisplatin-induced ERK activation was extracellular and intracellular Ca(2+)- 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 ERK 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.
我们研究了c-Jun氨基末端蛋白激酶（JNK）和细胞外信号调节蛋白激酶（ERK）级联反应在顺铂耐药的Caov-3和顺铂敏感的A2780人卵巢癌细胞系中的作用。用顺铂而非反铂异构体处理这两种细胞均可激活JNK和ERK。顺铂激活JNK发生在30分钟，3小时达到平台期，之后下降，而顺铂激活ERK呈双相模式，表明时间框架不同。顺铂激活JNK的最大浓度为1000 microM，而激活ERK的最大浓度为100 microM，更高浓度时激活程度降低，表明剂量依赖性不同。顺铂诱导的JNK激活既不依赖细胞外和细胞内Ca(2+)，也不依赖蛋白激酶C，而顺铂诱导的ERK激活依赖细胞外和细胞内Ca(2+)以及蛋白激酶C。丝裂原活化蛋白激酶/细胞外信号调节激酶激酶抑制剂PD98059对顺铂诱导的JNK活性无影响，表明ERK和JNK级联反应之间不存在相互作用。我们进一步研究了每个级联反应对顺铂处理后细胞活力的影响。在两种细胞中，显性负性c-Jun的外源性表达或用PD98059处理均可诱导对顺铂的敏感性。我们的研究结果表明，顺铂诱导的DNA损伤差异激活JNK和ERK级联反应，抑制其中任何一个级联反应均可使卵巢癌细胞对顺铂敏感。
