Inhibition of ATM blocks the etoposide-induced DNA damage response and apoptosis of resting human T cells

Korwek, Zbigniew; Sewastianik, Tomek; Bielak-Zmijewska, Anna; Mosieniak, Grazyna; Alster, Olga; Moreno-Villanueva, Maria; Bürkle, Alexander; Sikora, Ewa

Inhibition of ATM blocks the etoposide-induced DNA damage response and apoptosis of resting human T cells

Dateien

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Datum

2012

Autor:innen

Korwek, Zbigniew

Sewastianik, Tomek

Bielak-Zmijewska, Anna

Mosieniak, Grazyna

Alster, Olga

Moreno-Villanueva, Maria

Bürkle, Alexander

Sikora, Ewa

Open Access-Veröffentlichung

Open Access Green

Sammlungen

Biologie

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

DNA Repair. 2012, 11(11), pp. 864-873. ISSN 1568-7864. eISSN 1568-7856. Available under: doi: 10.1016/j.dnarep.2012.08.006

Zusammenfassung

It is believed that normal cells with an unaffected DNA damage response (DDR) and DNA damage repair machinery, could be less prone to DNA damaging treatment than cancer cells. However, the anticancer drug, etoposide, which is a topoisomerase II inhibitor, can generate DNA double strand breaks affecting not only replication but also transcription and therefore can induce DNA damage in non-replicating cells. Indeed, we showed that etoposide could influence transcription and was able to activate DDR in resting human T cells by inducing phosphorylation of ATM and its substrates, H2AX and p53. This led to activation of PUMA, caspases and to apoptotic cell death. Lymphoblastoid leukemic Jurkat cells, as cycling cells, were more sensitive to etoposide considering the level of DNA damage, DDR and apoptosis. Next, we used ATM inhibitor, KU 55933, which has been shown previously to be a radio/chemo-sensitizing agent. Pretreatment of resting T cells with KU 55933 blocked phosphorylation of ATM, H2AX and p53, which, in turn, prevented PUMA expression, caspase activation and apoptosis. On the other hand, KU 55933 incremented apoptosis of Jurkat cells. However, etoposide-induced DNA damage in resting T cells was not influenced by KU 55933 as revealed by the FADU assay. Altogether our results show that KU 55933 blocks DDR and apoptosis induced by etoposide in normal resting T cells, but increased cytotoxic effect on proliferating leukemic Jurkat cells. We discuss the possible beneficial and adverse effects of drugs affecting the DDR in cancer cells that are currently in preclinical anticancer trials.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Schlagwörter

FADU, γH2AX, DSBs, Caspases, KU 55933

Zitieren

ISO 690

KORWEK, Zbigniew, Tomek SEWASTIANIK, Anna BIELAK-ZMIJEWSKA, Grazyna MOSIENIAK, Olga ALSTER, Maria MORENO-VILLANUEVA, Alexander BÜRKLE, Ewa SIKORA, 2012. Inhibition of ATM blocks the etoposide-induced DNA damage response and apoptosis of resting human T cells. In: DNA Repair. 2012, 11(11), pp. 864-873. ISSN 1568-7864. eISSN 1568-7856. Available under: doi: 10.1016/j.dnarep.2012.08.006

BibTex

@article{Korwek2012-11-01Inhib-21719,
  year={2012},
  doi={10.1016/j.dnarep.2012.08.006},
  title={Inhibition of ATM blocks the etoposide-induced DNA damage response and apoptosis of resting human T cells},
  number={11},
  volume={11},
  issn={1568-7864},
  journal={DNA Repair},
  pages={864--873},
  author={Korwek, Zbigniew and Sewastianik, Tomek and Bielak-Zmijewska, Anna and Mosieniak, Grazyna and Alster, Olga and Moreno-Villanueva, Maria and Bürkle, Alexander and Sikora, Ewa},
  note={Corrigendum zu diesem Artikel: https://doi.org/10.1016/j.dnarep.2013.09.005}
}

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Kommentar zur Publikation

Corrigendum zu diesem Artikel: https://doi.org/10.1016/j.dnarep.2013.09.005

Universitätsbibliographie

Ja