Cisplatin-induced response of c-jun N-terminal kinase 1 and extracellular signal-regulated protein kinases 1 and 2 in a series of cisplatin-resistantovarian carcinoma cell lines

The cellular response to cisplatin involves activation of multiple signal t ransduction pathways, including the mitogen-activated protein (MAP) kinase pathways. In this study, we compared the cisplatin-induced activation of tw o MAP kinases, c-jun N-terminal kinase 1 (JNK1) and extracellular signal-re gulated protein kinases 1 and 2 (ERK1/2), in the cisplatin-sensitive ovaria n carcinoma cell line A2780 and its derivative cisplatin-resistant cell lin es CP70 and C200. Dose-dependent and time-dependent activation of JNK1 and ERK1/2 occurred in each of the three cell lines in response to cisplatin tr eatment. The requirement of higher concentrations of cisplatin for inductio n of maximum activation of JNK1 and ERK1/2 was correlated with increased le vels of cisplatin resistance. In addition, inhibition of cisplatin-induced ERK activation, using the MAP/ERK kinase 1 synthetic inhibitor PD98059, res ulted in enhanced sensitivity to cisplatin in ail three cell lines. These r esults suggest that cisplatin-induced ERK1/2 activity is not responsible fo r the acquired cisplatin resistance in CP70 and C200 cells but rather provi des a general cytoprotective effect in both cisplatin-sensitive and cisplat in-resistant cell lines. In conclusion, different patterns of cisplatin-ind uced JNK1 and ERK1/2 activation are observed in cell lines with different l evels of cisplatin sensitivity, and inhibition of cisplatin-induced ERK1/2 activation enhances sensitivity to cisplatin in both cisplatin-sensitive an d cisplatin-resistant cell lines. (C) 2000 Wiley-Liss, Inc.