Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe

Cornago Protomártir, Marta; Garcia-Alberich, C.; Blasco Angulo, Natividad; Vall-llaura Espinosa, Núria; Nàger Grifo, Mireia; Herreros Danés, Judit; Comella i Carnicé, Joan Xavier; Sanchis, Daniel; Llovera i Tomàs, Marta

doi:https://doi.org/10.1038/cddis.2014.412

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Issue date

2014-10-02

Author

Cornago Protomártir, Marta

Garcia-Alberich, C.

Blasco Angulo, Natividad

Vall-llaura Espinosa, Núria

Nàger Grifo, Mireia

Herreros Danés, Judit

Comella i Carnicé, Joan Xavier

Sanchis, Daniel

Llovera i Tomàs, Marta

Suggested citation

Cornago Protomártir, Marta; Garcia-Alberich, C.; Blasco Angulo, Natividad; Vall-llaura Espinosa, Núria; Nàger Grifo, Mireia; Herreros Danés, Judit; ... Llovera i Tomàs, Marta. (2014) . Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe. Cell Death & Disease, 2014, vol. 5, p. e1435. https://doi.org/10.1038/cddis.2014.412.

Abstract

Glioblastoma multiforme is resistant to conventional anti-tumoral treatments due to its infiltrative nature and capability of relapse; therefore, research efforts focus on characterizing gliomagenesis and identifying molecular targets useful on therapy. New therapeutic strategies are being tested in patients, such as Histone deacetylase inhibitors (HDACi) either alone or in combination with other therapies. Here two HDACi included in clinical trials have been tested, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), to characterize their effects on glioma cell growth in vitro and to determine the molecular changes that promote cancer cell death. We found that both HDACi reduce glioma cell viability, proliferation and clonogenicity. They have multiple effects, such as inducing the production of reactive oxygen species (ROS) and activating the mitochondrial apoptotic pathway, nevertheless cell death is not prevented by the pan-caspase inhibitor Q-VD-OPh. Importantly, we found that HDACi alter cell cycle progression by decreasing the expression of G2 checkpoint kinases Wee1 and checkpoint kinase 1 (Chk1). In addition, HDACi reduce the expression of proteins involved in DNA repair (Rad51), mitotic spindle formation (TPX2) and chromosome segregation (Survivin) in glioma cells and in human glioblastoma multiforme primary cultures. Therefore, HDACi treatment causes glioma cell entry into mitosis before DNA damage could be repaired and to the formation of an aberrant mitotic spindle that results in glioma cell death through mitotic catastrophe-induced apoptosis.

URI

http://hdl.handle.net/10459.1/48735

DOI

https://doi.org/10.1038/cddis.2014.412

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Cell Death & Disease, 2014, vol. 5, p. e1435

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Except where otherwise noted, this item's license is described as cc-by-nc-sa (c) Macmillan Publishers Limited, 2014