In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma.
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.
Mir
Shahryar E
SE
Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, VU University Medical Center, 1081 HV, Amsterdam, the Netherlands.
De Witt Hamer
Philip C
PC
Krawczyk
Przemek M
PM
Balaj
Leonora
L
Claes
An
A
Niers
Johanna M
JM
Van Tilborg
Angela A G
AA
Zwinderman
Aeilko H
AH
Geerts
Dirk
D
Kaspers
Gertjan J L
GJ
Peter Vandertop
W
W
Cloos
Jacqueline
J
Tannous
Bakhos A
BA
Wesseling
Pieter
P
Aten
Jacob A
JA
Noske
David P
DP
Van Noorden
Cornelis J F
CJ
Würdinger
Thomas
T
D054458:Amplified Fragment Length Polymorphism Analysis; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage; D004260:DNA Repair; D004195:Disease Models, Animal; D016195:G2 Phase / Q000502:physiology; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis; D008938:Mitosis / Q000502:physiology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C440869:PD 0166285; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human