1. ¹Department of Dermatology, Heinrich-Heine-University, Düsseldorf, Germany
2. ²Institute of Clinical Oncology, Heinrich-Heine-University, Düsseldorf, Germany
3. ³Institute of Pathology, Ruhr-University, Bochum, Germany

Correspondence: Professor Ulrich R. Hengge, Department of Dermatology, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany. E-mail: ulrich.hengge@uni-duesseldorf.de

Received 18 October 2006; Revised 14 March 2007; Accepted 18 March 2007; Published online 17 May 2007.

Abstract

Activation (phosphorylation) of mitogen-activated protein kinase (MAPK) signal transduction through BRAF and RAS causes a variety of functional effects including cell survival and cell death. In this study, we observed high extracellular signal-regulated kinase (ERK)1/2 phosphorylation levels in clinical melanoma metastases and various melanoma cell lines. Treatment of melanoma cell lines with cisplatin, a potent antitumor agent, increased the level of phosphorylated-ERK (P-ERK)1/2 and enhanced chemoresistance through activation of the cell survival protein 90-kDa ribosomal S6 kinase (RSK)1. The mitogen-activated protein kinase kinase (MEK) inhibitor (U0126) was able to block this effect and reduced cell viability and sensitized cells to cisplatin-induced apoptosis, as shown by PARP cleavage, caspase 3 expression, and annexin-V staining. In conclusion, the MAP kinase–ERK pathway is activated in melanoma and reduces the sensitivity of melanoma to cisplatin. Thus, inhibition of ERK1/2 in combination with selected chemotherapeutic agents may hold promise for more effective therapy of melanoma.