title: Cisplatin-induced response of c-jun N-terminal kinase 1 and extracellular signal--regulated protein kinases 1 and 2 in a series of cisplatin-resistant ovarian carcinoma cell lines.
abstract: The cellular response to cisplatin involves activation of multiple signal transduction pathways, including the mitogen-activated protein (MAP) kinase pathways. In this study, we compared the cisplatin-induced activation of two MAP kinases, c-jun N-terminal kinase 1 (JNK1) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), in the cisplatin-sensitive ovarian carcinoma cell line A2780 and its derivative cisplatin-resistant cell lines 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 treatment. The requirement of higher concentrations of cisplatin for induction of maximum activation of JNK1 and ERK1/2 was correlated with increased levels of cisplatin resistance. In addition, inhibition of cisplatin-induced ERK activation, using the MAP/ERK kinase 1 synthetic inhibitor PD98059, resulted in enhanced sensitivity to cisplatin in all three cell lines. These results suggest that cisplatin-induced ERK1/2 activity is not responsible for the acquired cisplatin resistance in CP70 and C200 cells but rather provides a general cytoprotective effect in both cisplatin-sensitive and cisplatin-resistant cell lines. In conclusion, different patterns of cisplatin-induced JNK1 and ERK1/2 activation are observed in cell lines with different levels of cisplatin sensitivity, and inhibition of cisplatin-induced ERK1/2 activation enhances sensitivity to cisplatin in both cisplatin-sensitive and cisplatin-resistant cell lines.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160-7332, USA.
authors.forename: W
authors.initials: W
authors.lastname: Cui
authors.forename: E M
authors.initials: EM
authors.lastname: Yazlovitskaya
authors.forename: M S
authors.initials: MS
authors.lastname: Mayo
authors.forename: J C
authors.initials: JC
authors.lastname: Pelling
authors.forename: D L
authors.initials: DL
authors.lastname: Persons
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one