Aim: 

Cisplatin (cisPt) is an effective DNA-damaging antitumor agent employed for the treatment of various cancers. We demonstrated previously that in malignant rat thyroid PC E1Araf cells cisPt activated MAPK/ERK which behaved as a prosurvival pathway. The aim of this study was to assess the role of epidermal growth factor receptor (EGFR) in cisPt response, since its involvement was showed in other cell types, and to determine whether EGFR mediates ERK activation provoked by cisPt.

Methods: 

PC E1Araf cells were incubated with cisPt with and without appropriate pharmacological inhibitors; western blotting of EGFR, MAPKs (ERK), PKB/Akt were made in order to perceive their involvement in the cisPt cellular response.

Results: 

The treatment of PC E1Araf cells with cisPt activates EGFR. Cells pre-treatment with EGFR inhibitor, AG1478 (15–30 mM), reduced cisPt induced ERK phophorylation and consequently increased cells sensitivity to cisPt. In addition, treatment of cells with cisPt provoked the phosphorylation of PKB/Akt. When the cells were pre-incubated with LY294002 (1–50 mM), a PI3K/Akt inhibitor, the number of surviving PC E1Araf cells after cisPt decreased significantly. Moreover, inhibition of PI3K/Akt also reduced cisPt-induced ERK activation. Cells pre-treatment with AG1478 completely inhibited the effects of cisPt on PKB/Akt activation. Finally, pre-incubation with both AG1478 and LY294002 before cisPt treatment had no additional effect on cell survival and ERK phosphorylation compared to the inhibitors alone.

Conclusion: 

In PC E1Araf cells cisPt resistance is partially mediated by EGFR through the activation of PKB/Akt which contributes to the phosphorylation of ERK induced by cisPt.