title: The nuclear translocation of ERK1/2 as an anticancer target.
abstract: A hallmark of the ERK1/2 functioning is their nuclear translocation, which is mainly required for the induction of proliferation. Activated ERK1/2 molecules that remain in the cytoplasm initiate other activities, including immediate feedback loops. Prevention of the nuclear translocation should therefore inhibit proliferation, without affecting cytoplasm-induced cellular processes. Here we present an NTS-derived myristoylated phosphomimetic peptide, which blocks the interaction of importin7 and ERK1/2, and consequently the nuclear translocation of the latter. In culture, the peptide induces apoptosis of melanoma cells inhibits the viability of other cancer cells, but has no effect on non-transformed, immortalized cells. It even inhibits the viability of PLX4032- and U0126-resistant melanoma cells. In xenograft models, the peptide inhibits several cancers, and acts much better than PLX4032 in preventing melanoma recurrence. This study provides a proof of concept for using the nuclear translocation of ERK1/2 as a drug target for the combat of various ERK1/2-related cancers.
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Plotnikov
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Karen
authors.initials: K
authors.lastname: Flores
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Galia
authors.initials: G
authors.lastname: Maik-Rachline
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Eldar
authors.initials: E
authors.lastname: Zehorai
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Einat
authors.initials: E
authors.lastname: Kapri-Pardes
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Berti
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Hanoch
authors.affiliation: The Ella Lemelbaum Institute for Melanoma, The Sheba Medical Center, Ramat Gan, and the Department of Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv 52621, Israel.
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Besser
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Rony
authors.initials: R
authors.lastname: Seger
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D016466:CHO Cells; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003412:Cricetulus; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008819:Mice, Nude; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D010455:Peptides / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
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