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

S.E. Mir; P.C. de Witt Hamer; P.M. Krawczyk; L. Balaj; A. Claes; J.M. Niers; A.A.G. Van Tilborg; A.H. Zwinderman; D. Geerts; G.J.L. Kaspers; W.P. Vandertop; J. Cloos; B.A. Tannous; P. Wesseling; J.A. Aten; D.P. Noske; C.J.F. van Noorden; T. 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

S.E. Mir, P.C. de Witt Hamer, P.M. Krawczyk, L. Balaj, A. Claes, J.M. Niers, A.A.G. Van Tilborg, A.H. Zwinderman, D. Geerts, G.J.L. Kaspers, W.P. Vandertop, J. Cloos, B.A. Tannous, P. Wesseling, J.A. Aten, D.P. Noske, C.J.F. van Noorden, T. Würdinger

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	244-57
Number of pages	14
Journal	Cancer Cell
Volume	18
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2010.08.011
Publication status	Published - 2010

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10.1016/j.ccr.2010.08.011

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Mir, S. E., de Witt Hamer, P. C., Krawczyk, P. M., Balaj, L., Claes, A., Niers, J. M., Van Tilborg, A. A. G., Zwinderman, A. H., Geerts, D., Kaspers, G. J. L., Vandertop, W. P., Cloos, J., Tannous, B. A., Wesseling, P., Aten, J. A., Noske, D. P., van Noorden, C. J. F., & Würdinger, T. (2010). In Silico Analysis of Kinase Expression Identifies WEE1 as a Gatekeeper against Mitotic Catastrophe in Glioblastoma. Cancer Cell, 18(3), 244-57. https://doi.org/10.1016/j.ccr.2010.08.011

@article{2842379b59a34c69bde8bdf8a0f1433d,

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

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.",

keywords = "Amplified Fragment Length Polymorphism Analysis, Animals, Cell Cycle/drug effects, Cell Cycle Proteins/antagonists & inhibitors, 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",

author = "S.E. Mir and {de Witt Hamer}, P.C. and P.M. Krawczyk and L. Balaj and A. Claes and J.M. Niers and {Van Tilborg}, A.A.G. and A.H. Zwinderman and D. Geerts and G.J.L. Kaspers and W.P. Vandertop and J. Cloos and B.A. Tannous and P. Wesseling and J.A. Aten and D.P. Noske and {van Noorden}, C.J.F. and T. W{\"u}rdinger",

year = "2010",

doi = "10.1016/j.ccr.2010.08.011",

language = "English",

volume = "18",

pages = "244--57",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "3",

}

Mir, SE, de Witt Hamer, PC, Krawczyk, PM, Balaj, L, Claes, A, Niers, JM, Van Tilborg, AAG, Zwinderman, AH, Geerts, D , Kaspers, GJL , Vandertop, WP , Cloos, J, Tannous, BA, Wesseling, P, Aten, JA, Noske, DP, van Noorden, CJF & Würdinger, T 2010, 'In Silico Analysis of Kinase Expression Identifies WEE1 as a Gatekeeper against Mitotic Catastrophe in Glioblastoma', Cancer Cell, vol. 18, no. 3, pp. 244-57. https://doi.org/10.1016/j.ccr.2010.08.011

TY - JOUR

T1 - In Silico Analysis of Kinase Expression Identifies WEE1 as a Gatekeeper against Mitotic Catastrophe in Glioblastoma

AU - Mir, S.E.

AU - de Witt Hamer, P.C.

AU - Krawczyk, P.M.

AU - Balaj, L.

AU - Claes, A.

AU - Niers, J.M.

AU - Van Tilborg, A.A.G.

AU - Zwinderman, A.H.

AU - Geerts, D.

AU - Kaspers, G.J.L.

AU - Vandertop, W.P.

AU - Cloos, J.

AU - Tannous, B.A.

AU - Wesseling, P.

AU - Aten, J.A.

AU - Noske, D.P.

AU - van Noorden, C.J.F.

AU - Würdinger, T.

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/drug effects

KW - Cell Cycle Proteins/antagonists & inhibitors

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 - 10.1016/j.ccr.2010.08.011

DO - 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 -