title: ERK1/2 is highly phosphorylated in melanoma metastases and protects melanoma cells from cisplatin-mediated apoptosis.
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.
authors.affiliation: Department of Dermatology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Alireza
authors.initials: A
authors.lastname: Mirmohammadsadegh
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Mota
authors.forename: Annett
authors.initials: A
authors.lastname: Gustrau
authors.forename: Mohammed
authors.initials: M
authors.lastname: Hassan
authors.forename: Sandeep
authors.initials: S
authors.lastname: Nambiar
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marini
authors.forename: Hans
authors.initials: H
authors.lastname: Bojar
authors.forename: Andrea
authors.initials: A
authors.lastname: Tannapfel
authors.forename: Ulrich R
authors.initials: UR
authors.lastname: Hengge
mesh_terms: 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*
chemical_list: D000970:Antineoplastic Agents; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002945:Cisplatin