title: The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma.
abstract: Anaplastic lymphoma kinase (ALK) is an important molecular target in neuroblastoma. Although tyrosine kinase inhibitors abrogating ALK activity are currently in clinical use for the treatment of ALK-positive (ALK(+)) disease, monotherapy with ALK tyrosine kinase inhibitors may not be an adequate solution for ALK(+) neuroblastoma patients. Increased expression of the gene encoding the transcription factor MYCN is common in neuroblastomas and correlates with poor prognosis. We found that the kinase ERK5 [also known as big mitogen-activated protein kinase (MAPK) 1 (BMK1)] is activated by ALK through a pathway mediated by phosphoinositide 3-kinase (PI3K), AKT, MAPK kinase kinase 3 (MEKK3), and MAPK kinase 5 (MEK5). ALK-induced transcription of MYCN and stimulation of cell proliferation required ERK5. Pharmacological or RNA interference-mediated inhibition of ERK5 suppressed the proliferation of neuroblastoma cells in culture and enhanced the antitumor efficacy of the ALK inhibitor crizotinib in both cells and xenograft models. Together, our results indicate that ERK5 mediates ALK-induced transcription of MYCN and proliferation of neuroblastoma, suggesting that targeting both ERK5 and ALK may be beneficial in neuroblastoma patients.
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Göteborg, Sweden.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Umapathy
authors.affiliation: Department of Molecular Biology, Building 6L, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Abeer
authors.initials: A
authors.lastname: El Wakil
authors.affiliation: Department of Molecular Biology, Building 6L, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Barbara
authors.initials: B
authors.lastname: Witek
authors.affiliation: The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5NG, UK.
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
authors.affiliation: The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5NG, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Danielson
authors.affiliation: School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China. Dana-Farber Cancer Institute, Harvard Medical School, Seeley G. Mudd Building, 628A, 250 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Seeley G. Mudd Building, 628A, 250 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Department of Radiation Sciences, Oncology, Umeå University, 901 87 Umea, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Department of Radiation Sciences, Oncology, Umeå University, 901 87 Umea, Sweden.
authors.forename: Samuel
authors.initials: S
authors.lastname: Kvarnbrink
authors.affiliation: Department of Molecular Biology, Building 6L, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Ruuth
authors.affiliation: Department of Molecular Biology, Building 6L, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Christina
authors.initials: C
authors.lastname: Schönherr
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Göteborg, Sweden. Department of Molecular Biology, Building 6L, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Palmer
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Göteborg, Sweden. bengt.hallberg@gu.se.
authors.forename: Bengt
authors.initials: B
authors.lastname: Hallberg
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins; D006801:Humans; D007091:Image Processing, Computer-Assisted; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008279:Magnetic Resonance Imaging; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000378:metabolism / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D016716:PC12 Cells; D034622:RNA Interference; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D049452:Green Fluorescent Proteins; C000626173:ALK protein, human; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D048054:Mitogen-Activated Protein Kinase 7