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Journal of Cancer Research and Clinical Oncology

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21.04.2017 | Original Article – Cancer Research

Deregulated BCL-2 family proteins impact on repair of DNA double-strand breaks and are targets to overcome radioresistance in lung cancer

verfasst von: Sarah A. Wieczorek, Frank Breitenbuecher, Aashish Soni, Katja Paul-Konietzko, Sophie Ziegler, Ali Sak, George Iliakis, Martin Schuler

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 9/2017

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Abstract

Purpose

DNA damage-induced cell death is a major effector mechanism of radiotherapy. Aberrant expression of anti-apoptotic BCL-2 family proteins is frequently observed in lung cancers. Against this background, we studied radioresistance mediated by BCL-2 family proteins at the mechanistic level and its potential as target for radiochemotherapy.

Methods

Lung cancer models stably expressing BCL-xL or MCL-1 were irradiated to study cell death, clonogenic survival, and DNA repair kinetics in vitro, and growth suppression of established tumors in vivo. Additionally, endogenous BCL-xL and MCL-1 were targeted by shRNA or pharmacologic agents prior to irradiation.

Results

Radiation exposure induced apoptosis at negligible levels. Yet, anti-apoptotic BCL-xL and MCL-1 expression conferred short-term and long-term radioresistance in vitro and in vivo. Radioresistance correlated with pertubations in homologous recombination repair and repair of DNA double-strand breaks by error-prone, alternative end-joining. Notably, genetic or pharmacologic targeting of BCL-xL or MCL-1 effectively sensitized lung cancer cells to radiotherapy.

Conclusions

In addition to directly suppressing apoptosis, BCL-2 family proteins confer long-term survival benefits to irradiated cancer cells associated with utilization of error-prone repair pathways. Targeting BCL-xL and MCL-1 is an attractive strategy for improving lung cancer radiotherapy.

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Titel: Deregulated BCL-2 family proteins impact on repair of DNA double-strand breaks and are targets to overcome radioresistance in lung cancer
verfasst von: Sarah A. Wieczorek
Frank Breitenbuecher
Aashish Soni
Katja Paul-Konietzko
Sophie Ziegler
Ali Sak
George Iliakis
Martin Schuler
Publikationsdatum: 21.04.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 9/2017
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-017-2427-1

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Deregulated BCL-2 family proteins impact on repair of DNA double-strand breaks and are targets to overcome radioresistance in lung cancer

Abstract

Purpose

Methods

Results

Conclusions

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Abstract

Purpose

Methods

Results

Conclusions

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