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Jan Asad

MYCN amplified neuroblastoma requires the mRNA translation regulator eEF2 kinase to adapt to nutrient deprivation

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  • Alberto Delaidelli, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
  • ,
  • Gian Luca Negri, Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, Canada.
  • ,
  • Asad Jan
  • Brandon Jansonius, Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, Canada.
  • ,
  • Amal El-Naggar, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
  • ,
  • Jonathan K M Lim, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
  • ,
  • Debjit Khan, Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.
  • ,
  • Htoo Zarni Oo, The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, Canada.
  • ,
  • Christopher J Carnie, Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, Canada.
  • ,
  • Marc Remke, Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Center (DKFZ), Heidelberg, Germany.
  • ,
  • John M Maris, Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, and the Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
  • ,
  • Gabriel Leprivier, Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
  • ,
  • Poul H Sorensen, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.

MYC family proteins are implicated in many human cancers, but their therapeutic targeting has proven challenging. MYCN amplification in childhood neuroblastoma (NB) is associated with aggressive disease and high mortality. Novel and effective therapeutic strategies are therefore urgently needed for these tumors. MYC-driven oncogenic transformation impairs cell survival under nutrient deprivation (ND), a characteristic stress condition within the tumor microenvironment. We recently identified eukaryotic Elongation Factor 2 Kinase (eEF2K) as a pivotal mediator of the adaptive response of tumor cells to ND. We therefore hypothesized that eEF2K facilitates the adaptation of MYCN amplified NB to ND, and that inhibiting this pathway can impair MYCN-driven NB progression. To test our hypothesis, we first analyzed publicly available genomic databases and tissue microarrays for eEF2K expression in NB, and for links between eEF2K, MYCN, and clinical outcome in NB. Effects of eEF2K inhibition were evaluated on survival of MYCN amplified versus non-amplified NB cell lines under ND. Finally, NB xenograft mouse models were used to confirm in vitro observations. Our results indicate that high eEF2K expression and activity are strongly predictive of poor outcome in NB, and correlates significantly with MYCN amplification. Inhibition of eEF2K markedly decreases survival of MYCN amplified NB cell lines in vitro under ND. Growth of MYCN amplified NB xenografts is markedly impaired by eEF2K knockdown, particularly under caloric restriction. In summary, eEF2K protects MYCN overexpressing NB cells from ND in vitro and in vivo, highlighting this kinase as a critical mediator of the adaptive response of MYCN amplified NB cells to metabolic stress.

OriginalsprogEngelsk
TidsskriftCell Death and Differentiation
Vol/bind24
Nummer9
Sider (fra-til)1564-1576
Antal sider13
ISSN1350-9047
DOI
StatusUdgivet - sep. 2017
Eksternt udgivetJa

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