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

doi:10.1016/j.ccr.2010.08.011

In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma

Cancer Cell. 2010 Sep 14;18(3):244-57. doi: 10.1016/j.ccr.2010.08.011.

Authors

Shahryar E Mir¹, 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

Affiliation

¹ Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, VU University Medical Center, 1081 HV, Amsterdam, the Netherlands.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Cell Cycle Proteins
Nuclear Proteins
PD 0166285
Pyrimidines
Tumor Suppressor Protein p53
Protein-Tyrosine Kinases
WEE1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding