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

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

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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 G₂ 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 G₂ 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.

Originele taal-2	Engels
Pagina's (van-tot)	244-257
Aantal pagina's	14
Tijdschrift	Cancer Cell
Volume	18
Nummer van het tijdschrift	3
DOI's	https://doi.org/10.1016/j.ccr.2010.08.011
Status	Gepubliceerd - sep. 2010
Extern gepubliceerd	Ja

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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., Peter Vandertop, W., 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), 244-257. https://doi.org/10.1016/j.ccr.2010.08.011

@article{157cb652e7a84642a110d47c3a4f466f,

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 G2 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 G2 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.",

author = "Mir, {Shahryar E.} and {De Witt Hamer}, {Philip C.} and Krawczyk, {Przemek M.} and Leonora Balaj and An Claes and Niers, {Johanna M.} and {Van Tilborg}, {Angela A.G.} and Zwinderman, {Aeilko H.} and Dirk Geerts and Kaspers, {Gertjan J.L.} and {Peter Vandertop}, W. and Jacqueline Cloos and Tannous, {Bakhos A.} and Pieter Wesseling and Aten, {Jacob A.} and Noske, {David P.} and {Van Noorden}, {Cornelis J.F.} and Thomas W{\"u}rdinger",

note = "Funding Information: This study was supported by grants from the Accelerate Brain Cancer Cure and the Dutch Cancer Society. We thank Z. Kwidama, L. Wedekind, M. Ubels, and W. Tigchelaar for technical assistance, S. Heukelom and P. Koken from the Department of Radiotherapy, VUmc, for use of the irradiation source, and J. Skog for CD133 analysis. ",

year = "2010",

month = sep,

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

language = "English",

volume = "18",

pages = "244--257",

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, Peter Vandertop, W, 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, nr. 3, blz. 244-257. 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, 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 - Peter Vandertop, W.

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 - Funding Information: This study was supported by grants from the Accelerate Brain Cancer Cure and the Dutch Cancer Society. We thank Z. Kwidama, L. Wedekind, M. Ubels, and W. Tigchelaar for technical assistance, S. Heukelom and P. Koken from the Department of Radiotherapy, VUmc, for use of the irradiation source, and J. Skog for CD133 analysis.

PY - 2010/9

Y1 - 2010/9

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 G2 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 G2 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 G2 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 G2 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.

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U2 - 10.1016/j.ccr.2010.08.011

DO - 10.1016/j.ccr.2010.08.011

M3 - Article

C2 - 20832752

AN - SCOPUS:77956517283

SN - 1535-6108

VL - 18

SP - 244

EP - 257

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

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

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