In Silico Analysis of Kinase Expression Identifies WEE1 as a Gatekeeper against Mitotic Catastrophe in Glioblastoma

Shahryar E. Mir, Philip C. de Witt Hamer, Przemek M. Krawczyk, Leonora Balaj, An Claes, Johanna M. Niers, Angela A. G. van Tilborg, Aeilko H. Zwinderman, Dirk Geerts, Gertjan J. L. Kaspers, W. Peter Vandertop, Jacqueline Cloos, Bakhos A. Tannous, Pieter Wesseling, Jacob A. Aten, David P. Noske, Cornelis J. F. van Noorden, Thomas Würdinger

Research output: Contribution to journalArticleAcademicpeer-review

238 Citations (Scopus)

Abstract

Kinases execute pivotal cellular functions and are therefore widely investigated as potential targets in anticancer treatment. Here we analyze the kinase gene expression profiles of various tumor types and reveal the wee1 kinase to be overexpressed in glioblastomas. We demonstrate that WEE1 is a major regulator of the G(2) checkpoint in glioblastoma cells. Inhibition of WEE1 by siRNA or small molecular compound in cells exposed to DNA damaging agents results in abrogation of the G(2) arrest, premature termination of DNA repair, and cell death. Importantly, we show that the small-molecule inhibitor of WEE1 sensitizes glioblastoma to ionizing radiation in vivo. Our results suggest that inhibition of WEE1 kinase holds potential as a therapeutic approach in treatment of glioblastoma
Original languageEnglish
Pages (from-to)244-257
Number of pages14
JournalCancer cell
Volume18
Issue number3
DOIs
Publication statusPublished - 2010

Keywords

  • Amplified Fragment Length Polymorphism Analysis
  • Animals
  • Cell Cycle Proteins/antagonists & inhibitors
  • Cell Cycle/drug effects
  • DNA Damage
  • DNA Repair
  • Disease Models, Animal
  • G2 Phase/physiology
  • Gene Expression Profiling
  • Glioblastoma/drug therapy
  • Humans
  • Mice
  • Mice, Nude
  • Microarray Analysis
  • Mitosis/physiology
  • Nuclear Proteins/antagonists & inhibitors
  • Protein-Tyrosine Kinases/antagonists & inhibitors
  • Pyrimidines/pharmacology
  • Tumor Suppressor Protein p53/genetics

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