title: The role of eIF4E in response and acquired resistance to vemurafenib in melanoma.
abstract: In eukaryotic cells, the rate-limiting component for cap-dependent mRNA translation is the translation initiation factor eIF4E. eIF4E is overexpressed in a variety of human malignancies, but whether it has a role in melanoma remains obscure. We hypothesized that eIF4E promotes melanoma cell proliferation and facilitates the development of acquired resistance to the BRAF inhibitor vemurafenib. We show that eIF4E is overexpressed in a panel of melanoma cell lines, compared with immortalized melanocytes. Knockdown of eIF4E significantly repressed the proliferation of a subset of melanoma cell lines. Moreover, in BRAF(V600E) melanoma cell lines, vemurafenib inhibits 4E-BP1 phosphorylation, thus promoting its binding to eIF4E. Cap-binding and polysome profiling analysis confirmed that vemurafenib stabilizes the eIF4E-4E-BP1 association and blocks mRNA translation, respectively. Conversely, in cells with acquired resistance to vemurafenib, there is an increased dependence on eIF4E for survival; 4E-BP1 is highly phosphorylated and thus eIF4E-4E-BP1 associations are impeded. Moreover, increasing eIF4E activity by silencing 4E-BP1/2 renders vemurafenib-responsive cells more resistant to BRAF inhibition. In conclusion, these data suggest that therapeutically targeting eIF4E may be a viable means of inhibiting melanoma cell proliferation and overcoming vemurafenib resistance.
authors.affiliation: Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dahabieh
authors.affiliation: Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.
authors.forename: Arjuna
authors.initials: A
authors.lastname: Rajakumar
authors.affiliation: Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
authors.forename: Monica C
authors.initials: MC
authors.lastname: Dobocan
authors.affiliation: Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
authors.forename: Marie-Noël
authors.initials: MN
authors.lastname: M'Boutchou
authors.affiliation: Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
authors.forename: Christophe
authors.initials: C
authors.lastname: Goncalves
authors.affiliation: Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.
authors.forename: Shiru L
authors.initials: SL
authors.lastname: Lucy
authors.affiliation: Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
authors.forename: Filippa
authors.initials: F
authors.lastname: Pettersson
authors.affiliation: Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada; Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Topisirovic
authors.affiliation: Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada; Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
authors.forename: Léon
authors.initials: L
authors.lastname: van Kempen
authors.affiliation: Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
authors.forename: Sonia V
authors.initials: SV
authors.lastname: Del Rincón
authors.affiliation: Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada; Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada. Electronic address: wmiller@ldi.jgh.mcgill.ca.
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D039561:Eukaryotic Initiation Factor-4E / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000473:pathology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf; D034741:RNA, Small Interfering / Q000494:pharmacology; D012878:Skin Neoplasms / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D007211:Indoles; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf