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

被引:167
作者
Hayakawa, J
Ohmichi, M
Kurachi, H
Ikegami, H
Kimura, A
Matsuoka, T
Jikihara, H
Mercola, D
Murata, Y
机构
[1] Osaka Univ, Sch Med, Dept Obstet & Gynecol, Suita, Osaka 5650871, Japan
[2] Univ Calif San Diego, Ctr Mol Genet, La Jolla, CA 92093 USA
关键词
D O I
10.1074/jbc.274.44.31648
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:31648 / 31654
页数:7
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