ERK1/2 is highly phosphorylated in melanoma metastases and protects melanoma cells from cisplatin-mediated apoptosis.
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.
Mirmohammadsadegh
Alireza
A
Department of Dermatology, Heinrich-Heine-University, Düsseldorf, Germany.
Mota
Rodrigo
R
Gustrau
Annett
A
Hassan
Mohammed
M
Nambiar
Sandeep
S
Marini
Alessandra
A
Bojar
Hans
H
Tannapfel
Andrea
A
Hengge
Ulrich R
UR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008954:Models, Biological; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*
D000970:Antineoplastic Agents; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002945:Cisplatin