TY - JOUR
T1 - In Silico Analysis of Kinase Expression Identifies WEE1 as a Gatekeeper against Mitotic Catastrophe in Glioblastoma
AU - Mir, Shahryar E.
AU - de Witt Hamer, Philip C.
AU - Krawczyk, Przemek M.
AU - Balaj, Leonora
AU - Claes, An
AU - Niers, Johanna M.
AU - van Tilborg, Angela A. G.
AU - Zwinderman, Aeilko H.
AU - Geerts, Dirk
AU - Kaspers, Gertjan J. L.
AU - Vandertop, W. Peter
AU - Cloos, Jacqueline
AU - Tannous, Bakhos A.
AU - Wesseling, Pieter
AU - Aten, Jacob A.
AU - Noske, David P.
AU - van Noorden, Cornelis J. F.
AU - Würdinger, Thomas
N1 - Copyright © 2010 Elsevier Inc. All rights reserved.
PY - 2010
Y1 - 2010
N2 - 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
AB - 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
KW - Amplified Fragment Length Polymorphism Analysis
KW - Animals
KW - Cell Cycle Proteins/antagonists & inhibitors
KW - Cell Cycle/drug effects
KW - DNA Damage
KW - DNA Repair
KW - Disease Models, Animal
KW - G2 Phase/physiology
KW - Gene Expression Profiling
KW - Glioblastoma/drug therapy
KW - Humans
KW - Mice
KW - Mice, Nude
KW - Microarray Analysis
KW - Mitosis/physiology
KW - Nuclear Proteins/antagonists & inhibitors
KW - Protein-Tyrosine Kinases/antagonists & inhibitors
KW - Pyrimidines/pharmacology
KW - Tumor Suppressor Protein p53/genetics
U2 - https://doi.org/10.1016/j.ccr.2010.08.011
DO - https://doi.org/10.1016/j.ccr.2010.08.011
M3 - Article
C2 - 20832752
SN - 1535-6108
VL - 18
SP - 244
EP - 257
JO - Cancer cell
JF - Cancer cell
IS - 3
ER -