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

Abstract

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 M, whereas activation of ERK was maximal at 100 M 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.

Novel platinum(IV) complexes induce rapid tumor cell death in vitro

“…25 On the other hand, some reports suggest ERK activation by cisplatin could antagonize apoptosis of tumor cells. [32][33][34] Interestingly, although complex 8 was able to induce ERK activation in our study, the failure of selective ERK inhibition to counteract the toxicity of this Pt(IV) complex argues against the involvement of ERK in its cytotoxic action. Our data instead suggest that overproduction of ROI, well known for its ability to trigger cell death, 35 might be crucial for the antitumor effect of novel Pt(IV) complexes.…”

Role of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumour cells

“…For example, ERK activation is reported to be necessary for cisplatin-induced apoptosis in lung cancer cells (Wang et al, 2000), cervical carcinoma cell lines (Wang et al, 2000;Yeh et al, 2002) and malignant TGCT cell lines (Schweyer et al, 2004a). In addition, inactivation of MEK/ERK by its inhibitors has been shown to prevent apoptosis in response to cisplatin leading to resistance (Wang et al, 2000;Yeh et al, 2002), although contradictory results have been reported (Hayakawa et al, 1999;Persons et al, 1999). In this study, we found that activation of the MEK/ERK pathway was associated with increased sensitivity to cisplatin-induced apoptosis in the cells with high levels of MAD2 expression (Figure 2).…”

Inhibition of Inhibitor of Nuclear Factor-κB Phosphorylation Increases the Efficacy of Paclitaxel in in Vitro and in Vivo Ovarian Cancer Models

“…Cell proliferation (36) was assessed by the addition of paclitaxel at the indicated concentrations for 48 hours 1 day after seeding test cells into 96-well plates. The number of surviving cells was determined 24 hours later by determination of A 490 of the dissolved formazan product after the addition of MTS {3-[4,5,dimethylthiazol-2-yl]-5-[3-carboxymethoxy-phenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt}for 1 hour as described by the manufacturer (Promega).…”