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

We have studied the roles of c-Jun N-terminal protein kinase (JNK) and extr acellular signal-regulated protein kinase (ERK) cascade in both the cisplat in-resistant Caov-5 and the cisplatin-sensitive A2780 human ovarian cancer cell Lines. Treatment of both cells with cisplatin but not transplatin isom er 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 f rame. Activation of JNK by cisplatin was maximal at 1000 mu M,whereas activ ation 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-dep endent, whereas cisplatin-induced ERK activation was extracellular and intr acellular Ca2+- dependent and protein kinase C-dependent. A mitogen-activat ed protein kinase/extracellular signal-regulated kinase kinase inhibitor, P D98059, 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 sugge st that cisplatin-induced DNA damage differentially activates JNK and ERK c ascades and that inhibition of either of these cascades sensitizes ovarian cancer cells to cisplatin.